BH3-Only Mimetics

  • Christine Alewine
Reference work entry


BH3 mimetics are a class of drugs designed to tip the balance of pro- and anti-apoptotic factors within a cell to favor apoptosis. They bind within a specific groove of anti-apoptotic Bcl-2 family survival factors in a similar manner to native proteins within the cell that regulate these factors. This primes the cell for apoptosis. Several small molecule BH3 mimetics are currently undergoing evaluation in clinical trials.


ABT-737 Anti-apoptotic Bcl-2 family Bad Bcl-2 ABT-737 and ABT-263 Assessment B-cell lymphoma and mantle cell lymphoma BH3-only mimetics BH3-only proteins Clinical trials CLL and ALL Gossypol Hydrocarbon stapling Mcl-1 overexpression Navitoclax Obatoclax Preclinical studies Role in cancer BH3-only proteins Activators Chemotherapy Overall survival in glioblastoma multiforme Predictors of survival Sensitizers Therapeutics Bid Bim Pro-apoptotic Bcl-2 proteins Puma and Noxa 


  1. Cartron PF, Loussouarn D, Campone M, Martin SA, Vallette FM. Prognostic impact of the expression/phosphorylation of the BH3-only proteins of the BCL-2 family in glioblastoma multiforme. Cell Death Dis. 2012;3:e421.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell. 2005;17:393–403.CrossRefPubMedGoogle Scholar
  3. Chiappori AA, Schreeder MT, Moezi MM, Stephenson JJ, Blakely J, Salgia R, Chu QS, Ross HJ, Subramaniam DS, Schnyder J, et al. A phase I trial of pan-Bcl-2 antagonist obatoclax administered as a 3-h or a 24-h infusion in combination with carboplatin and etoposide in patients with extensive-stage small cell lung cancer. Br J Cancer. 2012;106:839–45.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Cragg MS, Harris C, Strasser A, Scott CL. Unleashing the power of inhibitors of oncogenic kinases through BH3 mimetics. Nat Rev Cancer. 2009;9:321–6.CrossRefPubMedGoogle Scholar
  5. Craik AC, Veldhoen RA, Czernick M, Buckland TW, Kyselytzia K, Ghosh S, Lai R, Damaraju S, Underhill DA, Mackey JR, et al. The BH3-only protein Bad confers breast cancer taxane sensitivity through a nonapoptotic mechanism. Oncogene. 2010;29:5381–91.CrossRefPubMedGoogle Scholar
  6. Davids MS, Letai A. Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30:3127–35.CrossRefGoogle Scholar
  7. DeVita VT, Lawrence TS, Rosenberg SA. Cancer: principles & practice of oncology: primer of the molecular biology of cancer. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011.Google Scholar
  8. Elkholi R, Floros KV, Chipuk JE. The role of BH3-only proteins in tumor cell development, signaling, and treatment. Genes Cancer. 2011;2:523–37.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Happo L, Strasser A, Cory S. BH3-only proteins in apoptosis at a glance. J Cell Sci. 2012;125:1081–7.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Hartman ML, Czyz M. Pro-apoptotic activity of BH3-only proteins and BH3 mimetics: from theory to potential cancer therapy. Anti Cancer Agents Med Chem. 2012;12:966–81.CrossRefGoogle Scholar
  11. Heist RS, Fain J, Chinnasami B, Khan W, Molina JR, Sequist LV, Temel JS, Fidias P, Brainerd V, Leopold L, et al. Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2010;5:1637–43.Google Scholar
  12. Jiang N, Koh GS, Lim JY, Kham SK, Ariffin H, Chew FT, Yeoh AE. BIM is a prognostic biomarker for early prednisolone response in pediatric acute lymphoblastic leukemia. Exp Hematol. 2011;39:321–9. 329 e321-323.CrossRefPubMedGoogle Scholar
  13. Kelly PN, Strasser A. The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapy. Cell Death Differ. 2011;18:1414–24.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Khosravi-Far R, White E. Programmed cell death in cancer progression and therapy. Berlin: Springer; 2008.CrossRefGoogle Scholar
  15. Lessene G, Czabotar PE, Colman PM. BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov. 2008;7:989–1000.CrossRefPubMedGoogle Scholar
  16. Liu G, Kelly WK, Wilding G, Leopold L, Brill K, Somer B. An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2009;15:3172–6.CrossRefGoogle Scholar
  17. Lomonosova E, Chinnadurai G. BH3-only proteins in apoptosis and beyond: an overview. Oncogene. 2008;27 Suppl 1:S2–19.CrossRefPubMedPubMedCentralGoogle Scholar
  18. O’Brien SM, Claxton DF, Crump M, Faderl S, Kipps T, Keating MJ, Viallet J, Cheson BD. Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood. 2009;113:299–305.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Oki Y, Copeland A, Hagemeister F, Fayad LE, Fanale M, Romaguera J, Younes A. Experience with obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist in patients with relapsed or refractory classical Hodgkin lymphoma. Blood. 2012;119:2171–2.CrossRefPubMedGoogle Scholar
  20. Paik PK, Rudin CM, Pietanza MC, Brown A, Rizvi NA, Takebe N, Travis W, James L, Ginsberg MS, Juergens R, et al. A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer. Lung Cancer. 2011;74:481–5.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, Carney DA, He SZ, Huang DC, Xiong H, et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30:488–96.CrossRefGoogle Scholar
  22. Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR, Chu Q, Giaccone G, Khaira D, Ramalingam SS, et al. Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2012;18:3163–9.CrossRefGoogle Scholar
  23. Sinicrope FA, Rego RL, Foster NR, Thibodeau SN, Alberts SR, Windschitl HE, Sargent DJ. Proapoptotic Bad and Bid protein expression predict survival in stages II and III colon cancers. Clin Cancer Res Off J Am Assoc Cancer Res. 2008a;14:4128–33.CrossRefGoogle Scholar
  24. Sinicrope FA, Rego RL, Okumura K, Foster NR, O’Connell MJ, Sargent DJ, Windschitl HE. Prognostic impact of bim, puma, and noxa expression in human colon carcinomas. Clin Cancer Res Off J Am Assoc Cancer Res. 2008b;14:5810–8.CrossRefGoogle Scholar
  25. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202–8.CrossRefPubMedGoogle Scholar
  26. Walensky LD, Kung AL, Escher I, Malia TJ, Barbuto S, Wright RD, Wagner G, Verdine GL, Korsmeyer SJ. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science. 2004;305:1466–70.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, New York (outside the USA) 2017

Authors and Affiliations

  1. 1.Center for Cancer Research, National Cancer Institute, National Institutes of HealthBethesdaUSA

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