Journal ArticleDOI
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets
Andrew J. Souers,Joel D. Leverson,Erwin R. Boghaert,Scott L. Ackler,Nathaniel D. Catron,Jun Chen,Brian D. Dayton,Hong Ding,Sari H. Enschede,Wayne J. Fairbrother,David C.S. Huang,David C.S. Huang,Sarah G. Hymowitz,Sha Jin,Seong Lin Khaw,Seong Lin Khaw,Peter Kovar,Lloyd T. Lam,Jackie Lee,Heather Maecker,Kennan C. Marsh,Kylie D. Mason,Kylie D. Mason,Kylie D. Mason,Michael J. Mitten,Paul Nimmer,Anatol Oleksijew,Chang H. Park,Cheol-Min Park,Cheol-Min Park,Darren C. Phillips,Andrew W. Roberts,Andrew W. Roberts,Andrew W. Roberts,Deepak Sampath,John F. Seymour,John F. Seymour,Morey L. Smith,Gerard M. Sullivan,Stephen K. Tahir,Chris Tse,Michael D. Wendt,Yu Xiao,John Xue,Haichao Zhang,Rod A. Humerickhouse,Saul H. Rosenberg,Steven W. Elmore +47 more
TLDR
The re-engineering of navitoclax is reported to create a highly potent, orally bioavailable and BCL-2–selective inhibitor, ABT-199, which inhibits the growth of BCL–dependent tumors in vivo and spares human platelets, indicating that selective pharmacological inhibition of Bcl-2 shows promise for the treatment of B CL-2-dependent hematological cancers.Abstract:
Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.read more
Citations
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Journal ArticleDOI
Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy
TL;DR: The biochemical, structural and genetic studies that have clarified how the interplay between members of the BCL-2 family on mitochondria sets the apoptotic threshold are discussed, illuminating the physiological control of apoptosis, the pathological consequences of its dysregulation and the promising search for novel cancer therapies that target the BCA2 protein family.
Journal ArticleDOI
Idelalisib and rituximab in relapsed chronic lymphocytic leukemia.
Richard R. Furman,Jeff P. Sharman,Steven Coutre,Bruce D. Cheson,John M. Pagel,Peter Hillmen,Jacqueline C. Barrientos,Andrew D. Zelenetz,Thomas J. Kipps,Ian W. Flinn,Paolo Ghia,Herbert Eradat,Thomas J. Ervin,Nicole Lamanna,Bertrand Coiffier,Andrew R. Pettitt,Shuo Ma,Stephan Stilgenbauer,Paula Cramer,Maria Aiello,Dave Johnson,Langdon L. Miller,Daniel Li,Thomas Jahn,Roger Dansey,Michael Hallek,Susan O'Brien +26 more
TL;DR: The combination of idelalisib and rituximab, as compared with placebo and r ituximabs, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy.
Journal ArticleDOI
Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia
Andrew W. Roberts,Matthew S. Davids,John M. Pagel,Brad S. Kahl,Soham D. Puvvada,John F. Gerecitano,Thomas J. Kipps,Mary Ann Anderson,Mary Ann Anderson,Jennifer R. Brown,Lori A. Gressick,Shekman Wong,Martin Dunbar,Ming Zhu,Monali Desai,Elisa Cerri,Sari H. Enschede,Rod A. Humerickhouse,William G. Wierda,John F. Seymour,John F. Seymour +20 more
TL;DR: Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features.
Journal ArticleDOI
Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice.
Jianhui Chang,Yingying Wang,Yingying Wang,Lijian Shao,Remi-Martin Laberge,Marco Demaria,Judith Campisi,Judith Campisi,Krishnamurthy Janakiraman,Norman E. Sharpless,Sheng Ding,Wei Feng,Yi Luo,Xiaoyan Wang,Nukhet Aykin-Burns,Kimberly J. Krager,Usha Ponnappan,Martin Hauer-Jensen,Aimin Meng,Daohong Zhou +19 more
TL;DR: It is demonstrated that selective clearance of SCs by a pharmacological agent is beneficial in part through its rejuvenation of aged tissue stem cells, demonstrating that senolytic drugs may represent a new class of radiation mitigators and anti-aging agents.
Journal ArticleDOI
Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia
Courtney D. DiNardo,Brian A. Jonas,Vinod Pullarkat,Michael J. Thirman,Jacqueline S. Garcia,Andrew H. Wei,Marina Konopleva,Hartmut Döhner,Anthony Letai,Pierre Fenaux,Elizabeth A. Koller,Violaine Havelange,Brian Leber,Jordi Esteve,Jianxiang Wang,Vlatko Pejša,Roman Hájek,Kimmo Porkka,Árpád Illés,David Lavie,Roberto M. Lemoli,Kazuhito Yamamoto,Sung-Soo Yoon,Jun-Ho Jang,Su-Peng Yeh,Mehmet Turgut,Wan-Jen Hong,Ying Zhou,Jalaja Potluri,Keith W. Pratz +29 more
TL;DR: In previously untreated patients with confirmed AML who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received zsitidine alone.
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Journal ArticleDOI
An inhibitor of Bcl-2 family proteins induces regression of solid tumours
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