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Developing potent BTK^(C481S)PROTACs for ibrutinib-resistant malignant lymphoma

Chinese Chemical Letters 2023年第6期34卷 437-442页

作者： Yonghui Sun Xin Luo Zimo Yang Wenxing Lv Lixia Chen Hua Li Yu Rao MOE Key Laboratory of Protein Sciences School of Pharmaceutical SciencesMOE Key Laboratory of Bioorganic Phosphorus Chemistry&Chemical BiologyTsinghua UniversityBeijing 100084China Wuya College of Innovation Key Laboratory of Structure-Based Drug Design&DiscoveryMinistry of EducationShenyang Pharmaceutical UniversityShenyang110016China Institute of Structural Pharmacology&TCM Chemical Biology College of PharmacyFujian University of Traditional Chinese MedicineFuzhou 350122China

ibrutinib is a first-line treatment drug for B-cell malignancies.However,resistance to ibrutinib has been reported due to BTKC481Smutation.Although PROTAC strategy is expected to overcome this clinical resistance,it has limitations such as large molecular weight and moderate bioactivity,which restrict its potential clinical application.Herein,we report a new type of potent BTKC481S-targeting PROTAC degrader.Through design,computer-assisted optimization and SAR studies,we have developed a representative BTKC481Sdegrader L6 with a much smaller molecular weight and improved solubility.Notably,L6 demonstrates better BTK degrading activity and lower IC50value in ibrutinib-resistant cell line than the first-generation BTK degrader P13I.Optimization strategy of L6 provides a general approach in the development of PROTACs targeting BTK and other proteins for future study.

关键词： Drug design ibrutinib resistance BTK degraders PROTACs B-cell lymphoma

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A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-κB pathway

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Acta Pharmaceutica Sinica B 2023年第3期13卷 1093-1109页

作者： Sae-Bom Yoon Hyowon Hong Hee-Jong Lim Ji Hye Choi Yoon Pyo Choi Seong Wook Seo Hyuk Woo Lee Chong Hak Chae Woo-Kyu Park Hyun Young Kim Daeyoung Jeong Tran Quang De Chang-Seon Myung Heeyeong Cho Therapeutics&Biotechnology Division Korea Research Institute of Chemical TechnologyYuseong-guDaejeon 34114Republic of Korea Department of Pharmacology Chungnam National University College of PharmacyYuseong-guDaejeon 34134Republic of Korea Future Medicine Co. Ltd.Rm616 LH-Business Growth CenterSeongnamGyeonggido 13449Republic of Korea Department of Chemistry College of Natural SciencesCan Tho UniversityCan Tho city 9000Viet Nam

Interleukin-1 receptor-associated kinase 4(IRAK4)is a pivotal enzyme in the Toll-like receptor(TLR)/MYD88 dependent signaling pathway,which is highly activated in rheumatoid arthritis tissues and activated B cell-like diffuse large B-cell lymphoma(ABC-DLBCL).Inflammatory responses followed by IRAK4 activation promote B-cell proliferation and aggressiveness of lymphoma.Moreover,proviral integration site for Moloney murine leukemia virus 1(PIM1)functions as an anti-apoptotic kinase in propagation of ABC-DLBCL with ibrutinib resistance.We developed a dual IRAK4/PIM1 inhibitor KIC-0101 that potently suppresses the NF-κB pathway and proinflammatory cytokine induction in vitro and in vivo.In rheumatoid arthritis mouse models,treatment with KIC-0101 significantly ameliorated cartilage damage and inflammation.KIC-0101 inhibited the nuclear translocation of NF-κB and activation of JAK/STAT pathway in ABC-DLBCLs.In addition,KIC-0101 exhibited an anti-tumor effect on ibrutinib-resistant cells by synergistic dual suppression of TLR/MYD88-mediated NF-κB pathway and PIM1 kinase.Our results suggest that KIC-0101 is a promising drug candidate for autoimmune diseases and ibrutinib-resistant B-cell lymphomas.

关键词： Drug discovery IRAK4 PIM1 NF-κB pathway Rheumatoid arthritis ABC-DLBCL ibrutinib resistance Dual inhibitor

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