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한국응용약물학회> Biomolecules & Therapeutics(구 응용약물학회지)> Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

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Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

Krishna Babu Duggirala , Yujin Lee , Kwangho Lee
  • : 한국응용약물학회
  • : Biomolecules & Therapeutics(구 응용약물학회지) 30권1호
  • : 연속간행물
  • : 2022년 01월
  • : 19-27(9pages)
Biomolecules & Therapeutics(구 응용약물학회지)

DOI


목차

INTRODUCTION
CHRONICLES OF EGFR TKIS
CONCLUSION
ACKNOWLEDGMENTS
REFERENCES

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초록 보기

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in many cancers such as non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, and head and neck cancer. Mutations such as L858R in exon 21, exon 19 truncation (Del19), exon 20 insertions, and others are responsible for aberrant activation of EGFR in NSCLC. First-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have clinical benefits for EGFR-sensitive (L858R and Del19) NSCLC patients. However, after 10-12 months of treatment with these inhibitors, a secondary T790M mutation at the gatekeeper position in the kinase domain of EGFR was identified, which limited the clinical benefits. Second-generation EGFR irreversible inhibitors (afatinib and dacomitinib) were developed to overcome this T790M mutation. However, their lack of selectivity toward wild-type EGFR compromised their clinical benefits due to serious adverse events. Recently developed third-generation irreversible EGFR TKIs (osimertinib and lazertinib) are selective toward driving mutations and the T790M mutation, while sparing wildtype EGFR activity. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S, the key residue cysteine that forms covalent bonds with irreversible inhibitors. Because second- and thirdgeneration EGFR TKIs are irreversible inhibitors, they are not effective against C797S containing EGFR triple mutations (Del19/ T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism.

UCI(KEPA)

I410-ECN-0102-2022-500-000949612

간행물정보

  • : 의약학분야  > 약화학
  • : KCI등재
  • : SCOPUS
  • : 격월
  • : 1976-9148
  • : 2005-4483
  • : 학술지
  • : 연속간행물
  • : 1993-2022
  • : 1827


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1Modulation of Reactive Oxygen Species to Overcome 5-Fluorouracil Resistance

저자 : Kyung-soo Chun , Sang Hoon Joo

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 479-489 (11 pages)

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5-Fluorouracil (5-FU) remains to be an important chemotherapeutic drug for treating several cancers when targeted therapy is unavailable. Chemoresistance limits the clinical utility of 5-FU, and new strategies are required to overcome the resistance. Reactive oxygen species (ROS) and antioxidants are balanced differently in both normal and cancer cells. Modulating ROS can be one method of overcoming 5-FU resistance. This review summarizes selected compounds and endogenous cellular targets modulating ROS generation to overcome 5-FU resistance.

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2Senotherapeutics and Their Molecular Mechanism for Improving Aging

저자 : Jooho Park , Dong Wook Shin

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 490-500 (11 pages)

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Aging is defined as physiological dysfunction of the body and a key risk factor for human diseases. During the aging process, cellular senescence occurs in response to various extrinsic and intrinsic factors such as radiation-induced DNA damage, the activation of oncogenes, and oxidative stress. These senescent cells accumulate in many tissues and exhibit diverse phenotypes, such as resistance to apoptosis, production of senescence-associated secretory phenotype, cellular flattening, and cellular hypertrophy. They also induce abnormal dysfunction of the microenvironment and damage neighboring cells, eventually causing harmful effects in the development of various chronic diseases such as diabetes, cancer, and neurodegenerative diseases. Thus, pharmacological interventions targeting senescent cells, called senotherapeutics, have been extensively studied. These senotherapeutics provide a novel strategy for extending the health span and improving age-related diseases. In this review, we discuss the current progress in understanding the molecular mechanisms of senotherapeutics and provide insights for developing senotherapeutics.

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3p38 MAPK Inhibitor NJK14047 Suppresses CDNB-Induced Atopic Dermatitis-Like Symptoms in BALB/c Mice

저자 : Ju-hyun Lee , Seung-hwan Son , Nam-jung Kim , Dong-soon Im

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 501-509 (9 pages)

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Atopic dermatitis (AD) is a chronic inflammatory skin disorder. Suppression of MAPKs and NF-κB is implicated as a vital mechanism of action of several traditional Chinese medicines for AD therapy. Although overexpression of MAPK mRNA in the skin tissue has been shown in the AD model, the roles of each MAPK in AD pathogenesis have rarely been studied. This study examined the effect of NJK14047, an inhibitor of p38 MAPKs, on AD-like skin lesions induced in BALB/c mice by sensitization and challenges with 1-chloro-2,4-dinitrobenzene (CDNB) on dorsal skin and ears, respectively. After induction of AD, NJK14047 (2.5 mg/kg) or dexamethasone (10 mg/kg) was administrated for 3 weeks via intraperitoneal injection. Following its administration, NJK14047 suppressed CDNB-induced AD-like symptoms such as skin hypertrophy and suppressed mast cell infiltration into the skin lesions. It also reduced CDNB-induced increase in TH2 cytokine (IL-13) and TH1 cytokines (interferon-γ and IL-12A) levels but did not decrease serum IgE level. Furthermore, NJK14047 blocked CDNB-induced lymph node enlargement. These results suggest that NJK14047, a p38 MAPK inhibitor, might be an optimal therapeutic option with unique modes of action for AD treatment.

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4Effects of Dextran Sulfate Sodium-Induced Ulcerative Colitis on the Disposition of Tofacitinib in Rats

저자 : Sung Hun Bae , Hyo Sung Kim , Hyeon Gyeom Choi , Sun-young Chang , So Hee Kim

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 510-519 (10 pages)

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Tofacitinib, a Janus kinase 1 and 3 inhibitor, is mainly metabolized by CYP3A1/2 and CYP2C11 in the liver. The drug has been approved for the chronic treatment of severe ulcerative colitis, a chronic inflammatory bowel disease. This study investigated the pharmacokinetics of tofacitinib in rats with dextran sulfate sodium (DSS)-induced ulcerative colitis. After 1-min of intravenous infusion of tofacitinib (10 mg/kg), the area under the plasma concentration-time curves from time zero to time infinity (AUC) of tofacitinib significantly increased by 92.3%. The time-averaged total body clearance decreased significantly by 47.7% in DSS rats compared with control rats. After the oral administration of tofacitinib (20 mg/kg), the AUC increased by 85.5% in DSS rats. These results could be due to decreased intrinsic clearance of the drug caused by the reduction of CYP3A1/2 and CYP2C11 in the liver and intestine of DSS rats. In conclusion, ulcerative colitis inhibited CYP3A1/2 and CYP2C11 in the liver and intestines of DSS rats and slowed the metabolism of tofacitinib, resulting in increased plasma concentrations of tofacitinib in DSS rats.

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5AT9283, 1-Cyclopropyl-3-(3-(5-(Morpholinomethyl)-1H-Benzo[d] Imidazole-2-yl)-1H-Pyrazol-4-yl) Urea, Inhibits Syk to Suppress Mast Cell-Mediated Allergic Response

저자 : Su Jeong Kim , Min Yeong Choi , Keun Young Min , Min Geun Jo , Jie Min Kim , Hyung Sik Kim , Young Mi Kim

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 520-528 (9 pages)

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Mast cells are an effector cell that plays a pivotal role in type I hypersensitive immune responses. Mast cells exist in connective tissues, such as skin and mucosal tissue, and contain granules which contain bioactive substances such as histamine and heparin in cells. The granules of mast cells are secreted by antigen stimulation to cause the type I allergic hypersensitivity. In addition, stimulated by antigen, mast cells synthesize and secrete various eicosanoids and cytokines. While AT9283 is known to have anticancer effects, the therapeutic effect of AT9283 on allergic disorders is completely unknown. In this study, it was found that AT9283 reversibly inhibited antigen-IgE binding-induced degranulation in mast cells (IC50, approx. 0.58 μM) and suppressed the secretion of the inflammatory cytokines IL-4 (IC50, approx. 0.09 μM) and TNF-α (IC50, approx. 0.19 μM). For a mechanism of mast cell inhibition, while not inhibiting Syk phosphorylation, AT9283 suppressed the activation of LAT, a downstream substrate protein of Syk, in a dose-dependent manner. As expected, AT9283 also inhibited the activation of PLCγ1 and Akt, downstream signaling molecules of Syk/LAT, and MAP kinases such as JNK, Erk1/2, and P38. In an in vitro protein tyrosine kinase assay, AT9283 directly inhibited Syk activity. Next, AT9283 dose-dependently inhibited passive cutaneous anaphylaxis (PCA), an IgE-mediated allergic acute response, in mice (ED50, approx. 34 mg/kg, p.o.). These findings suggest that AT9283 has potential to use as a new drug for alleviating the symptoms of IgE-mediated allergic disorders.

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6A Novel Therapeutic Effect of a New Variant of CTLA4-Ig with Four Antennas That Are Terminally Capped with Sialic Acid in the CTLA4 Region

저자 : Yongwei Piao , So Yoon Yun , Hee Soo Kim , Bo Kyung Park , Hae Chan Ha , Zhicheng Fu , Ji Min Jang , Moon Jung Back , In Chul Shin , Jong Hoon Won , Dae Kyong Kim

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 529-539 (11 pages)

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Rheumatoid arthritis (RA) is a multifactorial immune-mediated disease, the pathogenesis of which involves different cell types. T-cell activation plays an important role in RA. Therefore, inhibiting T-cell activation is one of the current therapeutic strategies. Cytotoxic T-lymphocyte antigen 4-immunoglobulin (CTLA4-Ig), also known as abatacept, reduces cytokine secretion by inhibiting T-cell activation. To achieve a homeostatic therapeutic effect, CTLA4-Ig has to be administered repeatedly over several weeks, which limits its applicability in RA treatment. To overcome this limitation, we increased the number of sialic acid-capped antennas by genetically engineering the CTLA4 region to increase the therapeutic effect of CTLA4-Ig. N-acetylglucosaminyltransferase (GnT) and α2,6-sialyltransferase (α2,6-ST) were co-overexpressed in Chinese hamster ovary (CHO) cells to generate a highly sialylated CTLA4-Ig fusion protein, named ST6. The therapeutic and immunogenic effects of ST6 and CTLA4-Ig were compared. ST6 dose-dependently decreased paw edema in a mouse model of collagen-induced arthritis and reduced cytokine levels in a co-culture cell assay in a similar manner to CTLA4-Ig. ST6- and CTLA4-Ig-induced T cell-derived cytokines were examined in CD4 T cells isolated from peripheral blood mononuclear cells after cell killing through irradiation followed by flow- and magnetic-beadassisted separation. Interestingly, compared to CTLA4-Ig, ST6 was substantially less immunogenic and more stable and durable. Our data suggest that ST6 can serve as a novel, less immunogenic therapeutic strategy for patients with RA.

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7Betulin, an Anti-Inflammatory Triterpenoid Compound, Regulates MUC5AC Mucin Gene Expression through NF-kB Signaling in Human Airway Epithelial Cells

저자 : Rajib Hossain , Kyung-il Kim , Fengri Jin , Hyun Jae Lee , Choong Jae Lee

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 540-545 (6 pages)

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Betulin is a triterpenoid natural product contained in several medicinal plants including Betulae Cortex. These medicinal plants have been used for controlling diverse inflammatory diseases in folk medicine and betulin showed anti-inflammatory, antioxidative, and anticancer activities. In this study, we tried to examine whether betulin exerts a regulative effect on the gene expression of MUC5AC mucin under the status simulating a pulmonary inflammation, in human airway epithelial cells. Confluent NCI-H292 cells were pretreated with betulin for 30 min and then stimulated with phorbol 12-myristate 13-acetate (PMA) for 24 h or the indicated periods. The MUC5AC mucin mRNA expression and mucin glycoprotein production were measured by reverse transcription - polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. To elucidate the action mechanism of betulin, effect of betulin on PMA-induced nuclear factor kappa B (NF-kB) signaling pathway was also investigated by western blot analysis. The results were as follows: 1) Betulin significantly suppressed the production of MUC5AC mucin glycoprotein and down-regulated MUC5AC mRNA expression induced by PMA in NCI-H292 cells. 2) Betulin inhibited NF-κB activation stimulated by PMA. Suppression of inhibitory kappa B kinase (IKK) by betulin led to the inhibition of the phosphorylation and degradation of inhibitory kappa B alpha (IκBα), and the nuclear translocation of NF-κB p65. This, in turn, led to the down-regulation of MUC5AC glycoprotein production in NCI-H292 cells. These results suggest betulin inhibits the gene expression of mucin through regulation of NF-kB signaling pathway, in human airway epithelial cells.

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8Immune Responses to Plant-Derived Recombinant Colorectal Cancer Glycoprotein EpCAM-FcK Fusion Protein in Mice

저자 : Chae-yeon Lim , Deuk-su Kim , Yangjoo Kang , Ye-rin Lee , Kibum Kim , Do Sun Kim , Moon-soo Kim , Kisung Ko

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 546-552 (7 pages)

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Epidermal cell adhesion molecule (EpCAM) is a tumor-associated antigen (TAA), which has been considered as a cancer vaccine candidate. The EpCAM protein fused to the fragment crystallizable region of immunoglobulin G (IgG) tagged with KDEL endoplasmic reticulum (ER) retention signal (EpCAM-FcK) has been successfully expressed in transgenic tobacco (Nicotiana tabacum cv. Xanthi) and purified from the plant leaf. In this study, we investigated the ability of the plant-derived EpCAM-FcK (EpCAM-FcKP) to elicit an immune response in vivo. The animal group injected with the EpCAM-FcKP showed a higher differentiated germinal center (GC) B cell population (~9%) compared with the animal group injected with the recombinant rhEpCAM-Fc chimera (EpCAM-FcM). The animal group injected with EpCAM-FcKP (~42%) had more differentiated T follicular helper cells (Tfh) than the animal group injected with EpCAM-FcM (~7%). This study demonstrated that the plant-derived EpCAM-FcK fusion antigenic protein induced a humoral immune response in mice.

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9Growth Inhibitory and Pro-Apoptotic Effects of Hirsuteine in Chronic Myeloid Leukemia Cells through Targeting Sphingosine Kinase 1

저자 : Shan Gao , Tingting Guo , Shuyu Luo , Yan Zhang , Zehao Ren , Xiaona Lang , Gaoyong Hu , Duo Zuo , Wenqing Jia , Dexin Kong , Haiyang Yu , Yuling Qiu

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 553-566 (14 pages)

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Chronic myeloid leukemia (CML) is a slowly progressing hematopoietic cell disorder. Sphingosine kinase 1 (SPHK1) plays established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers, including leukemia. However, small-molecule inhibitors targeting SPHK1 in CML still need to be developed. This study revealed the role of SPHK1 in CML and investigated the potential anti-leukemic activity of hirsuteine (HST), an indole alkaloid obtained from the oriental plant Uncaria rhynchophylla, in CML cells. These results suggest that SPHK1 is highly expressed in CML cells and that overexpression of SPHK1 represents poor clinical outcomes in CML patients. HST exposure led to G2/M phase arrest, cellular apoptosis, and downregulation of Cyclin B1 and CDC2 and cleavage of Caspase 3 and PARP in CML cells. HST shifted sphingolipid rheostat from sphingosine 1-phosphate (S1P) towards the ceramide coupled with a marked inhibition of SPHK1. Mechanistically, HST significantly blocked SPHK1/S1P/S1PR1 and BCR-ABL/PI3K/Akt pathways. In addition, HST can be docked with residues of SPHK1 and shifts the SPHK1 melting curve, indicating the potential protein-ligand interactions between SPHK1 and HST in both CML cells. SPHK1 overexpression impaired apoptosis and proliferation of CML cells induced by HST alone. These results suggest that HST, which may serve as a novel and specific SPHK1 inhibitor, exerts anti-leukemic activity by inhibiting the SPHK1/S1P/ S1PR1 and BCR-ABL/PI3K/Akt pathways in CML cells, thus conferring HST as a promising anti-leukemic drug for CML therapy in the future.

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10Clinical Factors Affecting the Serum Retention of a Teratogenic Etretinate after the Acitretin Administration

저자 : Jong Heon Jeong , Gyu Hwan Hyun , Yu Jeong Park , Sung Won Kwon , Ai-young Lee

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 562-573 (12 pages)

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Etretinate, an acitretin metabolite, has a long retention duration in adipose tissues with a teratogenic potential. FDA advises a contraceptive period of at least three years after discontinuing acitretin. However, the effect of accumulated etretinate in adipose tissues on fetus is unknown. Although the teratogenic threshold for serum concentration of etretinate has been presented as higher than 2 ng/mL, that of acitretin is unknown. To examine factors affecting body retention of acitretin and etretinate, effects of acitretin dosage, acitretin-taking duration, elapsed time after stopping acitretin, age, sex, concomitant alcohol consumption, and foods and supplements rich in vitamin A intake on serum concentrations of acitretin and etretinate were analyzed in 14 acitretintaken patients and 58 controls without taking acitretin or etretinate. Serum concentrations of acitretin, but not etretinate, tended to be inversely related to the discontinuation duration. They were also related to old age. Different from a published result that alcohol consumption could promote the metabolism of acitretin into etretinate, alcohol intake did not affect serum concentrations of etretinate. Unexpectedly, more frequent intake of vitamin A or provitamin A-rich food and supplements was associated with higher serum acitretin, whereas less frequent intake of vitamin A or provitamin A-rich food and supplements was associated with higher serum levels of etretinate in acitretin-taken patients. Despite preliminary data, inter-individual variations in serum retention of etretinate suggest the necessity of further research before applying the same guidelines to everyone to minimize unnecessary contraception.

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1Inhibition of Cytochrome P450 Enzymes by Drugs―Molecular Basis and Practical Applications

저자 : F. Peter Guengerich

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 1호 발행 연도 : 2022 페이지 : pp. 1-18 (18 pages)

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Drug-drug interactions are a major cause of hospitalization and deaths related to drug use. A large fraction of these is due to inhibition of enzymes involved in drug metabolism and transport, particularly cytochrome P450 (P450) enzymes. Understanding basic mechanisms of enzyme inhibition is important, particularly in terms of reversibility and the use of the appropriate parameters. In addition to drug-drug interactions, issues have involved interactions of drugs with foods and natural products related to P450 enzymes. Predicting drug-drug interactions is a major effort in drug development in the pharmaceutical industry and regulatory agencies. With appropriate in vitro experiments, it is possible to stratify clinical drug-drug interaction studies. A better understanding of drug interactions and training of physicians and pharmacists has developed. Finally, some P450s have been the targets of drugs in some cancers and other disease states.

KCI등재SCOUPUS

2Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

저자 : Krishna Babu Duggirala , Yujin Lee , Kwangho Lee

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 1호 발행 연도 : 2022 페이지 : pp. 19-27 (9 pages)

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Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in many cancers such as non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, and head and neck cancer. Mutations such as L858R in exon 21, exon 19 truncation (Del19), exon 20 insertions, and others are responsible for aberrant activation of EGFR in NSCLC. First-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have clinical benefits for EGFR-sensitive (L858R and Del19) NSCLC patients. However, after 10-12 months of treatment with these inhibitors, a secondary T790M mutation at the gatekeeper position in the kinase domain of EGFR was identified, which limited the clinical benefits. Second-generation EGFR irreversible inhibitors (afatinib and dacomitinib) were developed to overcome this T790M mutation. However, their lack of selectivity toward wild-type EGFR compromised their clinical benefits due to serious adverse events. Recently developed third-generation irreversible EGFR TKIs (osimertinib and lazertinib) are selective toward driving mutations and the T790M mutation, while sparing wildtype EGFR activity. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S, the key residue cysteine that forms covalent bonds with irreversible inhibitors. Because second- and thirdgeneration EGFR TKIs are irreversible inhibitors, they are not effective against C797S containing EGFR triple mutations (Del19/ T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism.

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3Melatonin Protects Chronic Kidney Disease Mesenchymal Stem/Stromal Cells against Accumulation of Methylglyoxal via Modulation of Hexokinase-2 Expression

저자 : Gyeongyun Go , Yeo Min Yoon , Sungtae Yoon , Gaeun Lee , Ji Ho Lim , Su-yeon Han , Sang Hun Lee

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 1호 발행 연도 : 2022 페이지 : pp. 28-37 (10 pages)

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Treatment options for patients with chronic kidney disease (CKD) are currently limited; therefore, there has been significant interest in applying mesenchymal stem/stromal cell (MSC)-based therapy to treat CKD. However, MSCs harvested from CKD patients tend to show diminished viability and proliferation due to sustained exposure to uremic toxins in the CKD environment, which limits their utility for cell therapy. The application of melatonin has been demonstrated to improve the therapeutic efficacy of MSCs derived from and engrafted to tissues in patients suffering from CKD, although the underlying biological mechanism has not been elucidated. In this study, we observed overexpression of hexokinase-2 (HK2) in serum samples of CKD patients and MSCs harvested from an adenine-fed CKD mouse model (CKD-mMSCs). HK2 upregulation led to increased production levels of methylglyoxal (MG), a toxic metabolic intermediate of abnormal glycolytic processes. The overabundance of HK2 and MG was associated with impaired mitochondrial function and low cell proliferation in CKD-mMSCs. Melatonin treatment inhibited the increases in HK2 and MG levels, and further improved mitochondrial function, glycolytic metabolism, and cell proliferation. Our findings suggest that identifying and characterizing metabolic regulators such as HK2 in CKD may improve the efficacy of MSCs for treating CKD and other kidney disorders.

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4Lithocholic Acid Activates Mas-Related G Protein-Coupled Receptors, Contributing to Itch in Mice

저자 : Myung-hyun Song , Won-sik Shim

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 1호 발행 연도 : 2022 페이지 : pp. 38-47 (10 pages)

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The present study focused on lithocholic acid (LCA), a secondary bile acid that contributes to cholestatic pruritus. Although recent studies have found that LCA acts on MAS-related G protein-coupled receptor family member X4 (MRGPRX4) in humans, it is unclear which subtypes of MRGPRs are activated by LCA in mice since there is no precise ortholog of human MRGPRX4 in the mouse genome. Using calcium imaging, we found that LCA could activate mouse Mrgpra1 when transiently expressed in HEK293T cells. Moreover, LCA similarly activates mouse Mrgprb2. Importantly, LCA-induced responses showed dose-dependent effects through Mrgpra1 and Mrgprb2. Moreover, treatment with QWF (an antagonist of Mrgpra1 and Mrgprb2), YM254890 (Gαq inhibitor), and U73122 (an inhibitor of phospholipase C) significantly suppressed the LCA-induced responses, implying that the LCA-induced responses are indeed mediated by Mrgpra1 and Mrgprb2. Furthermore, LCA activated primary cultures of mouse sensory neurons and peritoneal mast cells, suggesting that Mrgpra1 and Mrgprb2 contribute to LCA-induced pruritus. However, acute injection of LCA did not induce noticeable differences in scratching behavior, implying that the pruritogenic role of LCA may be marginal in non-cholestatic conditions. In summary, the present study identified for the first time that LCA can activate Mrgpra1 and Mrgprb2. The current findings provide further insight into the similarities and differences between human and mouse MRGPR families, paving a way to understand the complex roles of these pruriceptors.

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5Novel GPR43 Agonists Exert an Anti-Inflammatory Effect in a Colitis Model

저자 : Bi-oh Park , Jong Soon Kang , Suresh Paudel , Sung Goo Park , Byoung Chul Park , Sang-bae Han , Young-shin Kwak , Jeong-hoon Kim , Sunhong Kim

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 1호 발행 연도 : 2022 페이지 : pp. 48-54 (7 pages)

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GPR43 (also known as FFAR2), a metabolite-sensing G-protein-coupled receptor stimulated by short-chain fatty acid (SCFA) ligands is involved in innate immunity and metabolism. GPR43 couples with Gαi/o and Gαq/11 heterotrimeric proteins and is capable of decreasing cyclic AMP and inducing Ca2+ flux. The GPR43 receptor has additionally been shown to bind β-arrestin 2 and inhibit inflammatory pathways, such as NF-κB. However, GPR43 shares the same ligands as GPR41, including acetate, propionate, and butyrate, and determination of its precise functions in association with endogenous ligands, such as SCFAs alone, therefore remains a considerable challenge. In this study, we generated novel synthetic agonists that display allosteric modulatory effects on GPR43 and downregulate NF-κB activity. In particular, the potency of compound 187 was significantly superior to that of preexisting compounds in vitro. However, in the colitis model in vivo, compound 110 induced more potent attenuation of inflammation. These novel allosteric agonists of GPR43 clearly display anti-inflammatory potential, supporting their clinical utility as therapeutic drugs.

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6Oleanolic Acid Provides Neuroprotection against Ischemic Stroke through the Inhibition of Microglial Activation and NLRP3 Inflammasome Activation

저자 : Arjun Sapkota , Ji Woong Choi

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 1호 발행 연도 : 2022 페이지 : pp. 55-63 (9 pages)

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Oleanolic acid (OA), a natural pentacyclic triterpenoid, has been reported to exert protective effects against several neurological diseases through its anti-oxidative and anti-inflammatory activities. The goal of the present study was to evaluate the therapeutic potential of OA against acute and chronic brain injuries after ischemic stroke using a mouse model of transient middle cerebral artery occlusion (tMCAO, MCAO/reperfusion). OA administration immediately after reperfusion significantly attenuated acute brain injuries including brain infarction, functional neurological deficits, and neuronal apoptosis. Moreover, delayed administration of OA (at 3 h after reperfusion) attenuated brain infarction and improved functional neurological deficits during the acute phase. Such neuroprotective effects were associated with attenuation of microglial activation and lipid peroxidation in the injured brain after the tMCAO challenge. OA also attenuated NLRP3 inflammasome activation in activated microglia during the acute phase. In addition, daily administration of OA for 7 days starting from either immediately after reperfusion or 1 day after reperfusion significantly improved functional neurological deficits and attenuated brain tissue loss up to 21 days after the tMCAO challenge; these findings supported therapeutic effects of OA against ischemic stroke-induced chronic brain injury. Together, these findings showed that OA exerted neuroprotective effects against both acute and chronic brain injuries after tMCAO challenge, suggesting that OA is a potential therapeutic agent to treat ischemic stroke.

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7Vinyl-Stilbene Inhibits Human Norovirus RNA Replication by Activating Heat-Shock Factor-1

저자 : Ahrim Lee , Jieun Sung , Dipesh S. Harmalkar , Hyeseul Kang , Hwayoung Lee , Kyeong Lee , Choongho Lee

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 1호 발행 연도 : 2022 페이지 : pp. 64-71 (8 pages)

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Norovirus (NV) is the most common cause of viral gastroenteritis, with the potential to develop into a fatal disease in those who are immuno-compromised, and effective vaccines and treatments are still non-existent. In this study, we aimed to elucidate the molecular mechanism of the previously identified NV replication inhibitor utilizing a vinyl-stilbene backbone, AC-1858. First, we confirmed the inhibition of the NV RNA replication by a structural analog of AC-1858, AC-2288 with its exclusive cytoplasmic subcellular localization. We further validated the induction of one specific host factor, the phosphorylated form of heat shock factor (HSF)-1, and its increased nuclear localization by AC-1858 treatment. Finally, we verified the positive and negative impact of the siRNA-mediated downregulation and lentivirus-mediated overexpression of HSF-1 on NV RNA replication. In conclusion, these data suggest the restrictive role of the host factor HSF-1 in overall viral RNA genome replication during the NV life cycle.

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8Licochalcone H Induces Cell Cycle Arrest and Apoptosis in Human Skin Cancer Cells by Modulating JAK2/STAT3 Signaling

저자 : Kyung-ho Park , Sang Hoon Joo , Ji-hye Seo , Jumi Kim , Goo Yoon , Young-joo Jeon , Mee-hyun Lee , Jung-il Chae , Woo-keun Kim , Jung-hyun Shim

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 1호 발행 연도 : 2022 페이지 : pp. 72-79 (8 pages)

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Licochalcone H (LCH) is a phenolic compound synthetically derived from licochalcone C (LCC) that exerts anticancer activity. In this study, we investigated the anticancer activity of LCH in human skin cancer A375 and A431 cells. The 3-(4,5-dimethylthiazol- 2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) cell viability assay was used to evaluate the antiproliferative activity of LCH. Cell cycle distribution and the induction of apoptosis were analyzed by flow cytometry. Western blotting assays were performed to detect the levels of proteins involved in cell cycle progression, apoptosis, and the JAK2/STAT3 signaling pathway. LCH inhibited the growth of cells in dose- and time-dependent manners. The annexin V/propidium iodide double staining assay revealed that LCH induced apoptosis, and the LCH-induced apoptosis was accompanied by cell cycle arrest in the G1 phase. Western blot analysis showed that the phosphorylation of JAK2 and STAT3 was decreased by treatment with LCH. The inhibition of the JAK2/STAT3 signaling pathway by pharmacological inhibitors against JAK2/STAT3 (cryptotanshinone (CTS) and S3I-201) simulated the antiproliferative effect of LCH suggesting that LCH induced apoptosis by modulating JAK2/STAT3 signaling.

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9Enhancement of Radiosensitivity by DNA Hypomethylating Drugs through Apoptosis and Autophagy in Human Sarcoma Cells

저자 : Moon-taek Park , Sung-dae Kim , Yu Kyeong Han , Jin Won Hyun , Hae-june Lee , Joo Mi Yi

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 1호 발행 연도 : 2022 페이지 : pp. 80-89 (10 pages)

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The targeting of DNA methylation in cancer using DNA hypomethylating drugs has been well known to sensitize cancer cells to chemotherapy and immunotherapy by affecting multiple pathways. Herein, we investigated the combinational effects of DNA hypomethylating drugs and ionizing radiation (IR) in human sarcoma cell lines both in vitro and in vivo. Clonogenic assays were performed to determine the radiosensitizing properties of two DNA hypomethylating drugs on sarcoma cell lines we tested in this study with multiple doses of IR. We analyzed the effects of 5-aza-dC or SGI-110, as DNA hypomethylating drugs, in combination with IR in vitro on the proliferation, apoptosis, caspase-3/7 activity, migration/invasion, and Western blotting using apoptosis- or autophagy-related factors. To confirm the combined effect of DNA hypomethylating drugs and IR in our in vitro experiment, we generated the sarcoma cells in nude mouse xenograft models. Here, we found that the combination of DNA hypomethylating drugs and IR improved anticancer effects by inhibiting cell proliferation and by promoting synergistic cell death that is associated with both apoptosis and autophagy in vitro and in vivo. Our data demonstrated that the combination effects of DNA hypomethylating drugs with radiation exhibited greater cellular effects than the use of a single agent treatment, thus suggesting that the combination of DNA hypomethylating drugs and radiation may become a new radiotherapy to improve therapeutic efficacy for cancer treatment.

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10Botulinum Toxin A Ameliorates Neuroinflammation in the MPTP and 6-OHDA-Induced Parkinson's Disease Models

저자 : Hyeon Joo Ham , In Jun Yeo , Seong Hee Jeon , Jun Hyung Lim , Sung Sik Yoo , Dong Ju Son , Sung-su Jang , Haksup Lee , Seung-jin Shin , Sang Bae Han , Jae Suk Yun , Jin Tae Hong

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 1호 발행 연도 : 2022 페이지 : pp. 90-97 (8 pages)

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Recently, increasing evidence suggests that neuroinflammation may be a critical factor in the development of Parkinson's disease (PD) in addition to the ratio of acetylcholine/dopamine because dopaminergic neurons are particularly vulnerable to inflammatory attack. In this study, we investigated whether botulinum neurotoxin A (BoNT-A) was effective for the treatment of PD through its anti-neuroinflammatory effects and the modulation of acetylcholine and dopamine release. We found that BoNT-A ameliorated MPTP and 6-OHDA-induced PD progression, reduced acetylcholine release, levels of IL-1β, IL-6 and TNF-α as well as GFAP expression, but enhanced dopamine release and tyrosine hydroxylase expression. These results indicated that BoNT-A had beneficial effects on MPTP or 6-OHDA-induced PD-like behavior impairments via its anti-neuroinflammation properties, recovering dopamine, and reducing acetylcholine release.

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