The B cell lymphoma 2(BCL2)protein family critically controls apoptosis by regulating the release of cytochrome c from mitochondria.In this cutting-edge review,we summarize the basic biology regulating the BCL2 family...The B cell lymphoma 2(BCL2)protein family critically controls apoptosis by regulating the release of cytochrome c from mitochondria.In this cutting-edge review,we summarize the basic biology regulating the BCL2 family including canonical and noncanonical functions,and highlight milestones from basic research to clinical applications in cancer and other pathophysiological conditions.We review laboratory and clinical development of BH3-mimetics as well as more recent approaches including proteolysis targeting chimeras(PROTACs),antibody-drug conjugates(ADCs)and tools targeting the BH4 domain of BCL2.The first BCL2-selective BH3-mimetic,venetoclax,showed remarkable efficacy with manageable toxicities and has transformed the treatment of several hematologic malignancies.Following its success,several chemically similar BCL2 inhibitors such as sonrotoclax and lisaftoclax are currently under clinical evaluation,alone and in combination.Genetic analysis highlights the importance of BCLX,and MCL1 across different cancer types and the possible utility of BH3-mimetics targeting these proteins.However,the development of BH3-mimetics targeting BCL-X_(L) or MCL1 has been more challenging,with on-target toxicities including thrombocytopenia for BCL-X_(L) and cardiac toxicities for MCL1 inhibitors precluding clinical development.Tumor-specific BCL-X_(L) or MCL1 inhibition may be achieved by novel targeting approaches using PROTACs or selective drug delivery strategies and would be transformational in many subtypes of malignancy.Taken together,we envision that the targeting of BCL2 proteins,while already a success story of translational research,may in the foreseeable future have broader clinical applicability and improve the treatment of multiple diseases.展开更多
基金supported by the Deutsche Krebshilfe(to M.V.)the Wilhelm Sander Stiftung(to M.V.)+13 种基金the Deutsche Kinderkrebsstiftung(to M.V)the Deutsche Jose Carreras Leukamie-Stiftung(to M.V and S.M.)research funding from LOxO(to V.M.S)Y.B.is supported by a Junior Clinician Scientist grant of the Goethe-University Frankfurt and by funds of the Rudolf-GeiBendorfer-StiftungWork in MJSD lab is supported by funds from the Scott-Waudby Trustthe Hope Against Cancer charity,Cancer Research UK in conjunction with the UK Department of Health on an Experimental Cancer Medicine Center grant[MRC]by Leicester Drug Discovery and Diagnostics under the University of Leicester Institute for Precision Health[MRC-Impact Acceleration AccountMR/X502777/1]is carried out at the National Institute for Health and Care Research(NIHR)Leicester Biomedical Research Center(BRC).Additional funding was obtained from Beigene and LOXO pharmaWork in the G.B.lab is funded by grants from the Research Foundation Flanders(GOE7520N,G081821N and G094522 N)from the Research Council,KU Leuven(C14/19/099)the Central European Leuven Strategic Alliance(CELSA/23/031and CELSA/23/032)GB is member of the FWO Scientific Research Network CaSign(W0.014.22N)MC(application number 11K7122N)and TV(application number:12ZG121N)were supported by fellowships from the Research Foundation FlandersWork in SM lab is supported by project PI20/00328 from the Instituto de Salud Carlos ll(Spain)and the M.C.AndreuMemorialFund.
文摘The B cell lymphoma 2(BCL2)protein family critically controls apoptosis by regulating the release of cytochrome c from mitochondria.In this cutting-edge review,we summarize the basic biology regulating the BCL2 family including canonical and noncanonical functions,and highlight milestones from basic research to clinical applications in cancer and other pathophysiological conditions.We review laboratory and clinical development of BH3-mimetics as well as more recent approaches including proteolysis targeting chimeras(PROTACs),antibody-drug conjugates(ADCs)and tools targeting the BH4 domain of BCL2.The first BCL2-selective BH3-mimetic,venetoclax,showed remarkable efficacy with manageable toxicities and has transformed the treatment of several hematologic malignancies.Following its success,several chemically similar BCL2 inhibitors such as sonrotoclax and lisaftoclax are currently under clinical evaluation,alone and in combination.Genetic analysis highlights the importance of BCLX,and MCL1 across different cancer types and the possible utility of BH3-mimetics targeting these proteins.However,the development of BH3-mimetics targeting BCL-X_(L) or MCL1 has been more challenging,with on-target toxicities including thrombocytopenia for BCL-X_(L) and cardiac toxicities for MCL1 inhibitors precluding clinical development.Tumor-specific BCL-X_(L) or MCL1 inhibition may be achieved by novel targeting approaches using PROTACs or selective drug delivery strategies and would be transformational in many subtypes of malignancy.Taken together,we envision that the targeting of BCL2 proteins,while already a success story of translational research,may in the foreseeable future have broader clinical applicability and improve the treatment of multiple diseases.
