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-XL), which has shown clinical efficacy in some BCL-2–dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-XL 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.

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We thank M. Bruncko, E. Fry, L. Hasvold, L. Hexamer, A. Kunzer, A. Petros, X. Song, Z. Tao, L. Wang and X. Wang for contributions to the generation of ABT-199 and related analogs and J. Bouska, and D. Osterling for analytical support. The authors acknowledge G. Chiang and A. Vasudevan for critical reading of this manuscript, L. Belmont, I. Wertz, J. Adams, S. Cory, P. Colman, P. Czabotar and G. Lessene for useful discussions and K. Lowes, E. Litvinovich and L. Roberts for technical analysis. Research performed at the Walter and Eliza Hall Institute (WEHI) was supported by grants and fellowships from the Australian National Health and Medical Research Council (NHMRC, including an Independent Research Institutes Infrastructure Support Scheme (IRIISS) grant), the Australian Cancer Research Foundation, the Leukaemia Foundation of Australia, the Cancer Council of Victoria, the Victorian Cancer Agency, the Victorian State Government Operational Infrastructure Support and the Leukemia Lymphoma Society. The authors acknowledge L.M. Staudt (US National Institutes of Health) for DLBCL cell lines.

Author information

Author notes

    • Cheol-Min Park

    Present address: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore.


  1. AbbVie Inc., North Chicago, Illinois, USA.

    • 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
    • , Sha Jin
    • , Peter J Kovar
    • , Lloyd T Lam
    • , Kennan C Marsh
    • , Michael J Mitten
    • , Paul M Nimmer
    • , Anatol Oleksijew
    • , Chang H Park
    • , Cheol-Min Park
    • , Darren C Phillips
    • , Morey L Smith
    • , Gerard M Sullivan
    • , Stephen K Tahir
    • , Chris Tse
    • , Michael D Wendt
    • , Yu Xiao
    • , John C Xue
    • , Haichao Zhang
    • , Rod A Humerickhouse
    • , Saul H Rosenberg
    •  & Steven W Elmore
  2. Genentech, Inc., South San Francisco, California, USA.

    • Wayne J Fairbrother
    • , Sarah G Hymowitz
    • , Jackie Lee
    • , Heather L Maecker
    •  & Deepak Sampath
  3. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

    • David C S Huang
    • , Seong Lin Khaw
    • , Kylie D Mason
    •  & Andrew W Roberts
  4. Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.

    • David C S Huang
    • , Seong Lin Khaw
    • , Kylie D Mason
    • , Andrew W Roberts
    •  & John F Seymour
  5. Department of Clinical Hematology and Bone Marrow Transplantation, Royal Melbourne Hospital, Parkville, Victoria, Australia.

    • Kylie D Mason
    •  & Andrew W Roberts
  6. Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

    • John F Seymour


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A.J.S., S.W.E., S.H.R., S.G.H., W.J.F., D.C.S.H., J.D.L. and C.T. directed aspects of the preclinical research. A.J.S. and J.D.L. interpreted data and wrote the manuscript. A.W.R., S.H.E., J.F.S. and R.A.H. directed the clinical trial design, generated patient data and interpreted results, and A.W.R. contributed in writing the manuscript. S.L.K. generated in vitro CLL experiments. K.D.M. generated in vitro normal volunteer platelet data. M.J.M., E.R.B., S.L.A., D.S., H.L.M., J.L. and A.O. generated in vivo pharmacology data, and E.R.B. contributed in writing of the manuscript. M.D.W., C.-M.P., G.M.S., H.D. and A.J.S. conceived of or generated the compounds described in the manuscript. C.H.P. generated the X-ray structures. J.D.L., D.C.P., S.J., S.K.T., J.C., J.C.X., P.M.N., Y.X., H.Z., P.J.K., C.T., L.T.L. and M.L.S. performed the biological characterization of ABT-199 and other compounds described in the manuscript. N.D.C., B.D.D. and K.C.M. generated the pharmacokinetic and platelet data in conscious dogs.

Competing interests

A.J.S., J.D.L., E.R.B., S.L.A., N.D.C., J.C., H.D., S.H.E., S.J., P.J.K., L.T.L., K.C.M., M.J.M., P.M.N., A.O., C.H.P., D.C.P., M.L.S., G.M.S., S.K.T., C.T., M.D.W., Y.X., J.C.X., H.Z., R.A.H., S.H.R. and S.W.E. are employees and stockholders of Abbott Laboratories. W.J.F., S.G.H., H.L.M. and D.S. are employees of Genentech, Inc., a member of the Roche group, and are stockholders of Roche Holding, AG. D.C.S.H., S.L.K., K.D.M. and A.W.R. are employees of Walter and Eliza Hall Institute, which receives commercial income and research funding from Genentech, Inc. and Abbott Laboratories.

Corresponding author

Correspondence to Andrew J Souers.

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