The challenge of drugging undruggable targets in cancer: Lessons learned from targeting BCL-2 family members

Clinical Cancer Research

Volumn 13, Issue 24, 2007, Pages 7264-7270

  Verdine, Gregory L ^a,c,d   Walensky, Loren D ^b,c  

^a HARVARD UNIVERSITY   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c DANA FARBER CANCER INSTITUTE   (United States)

^d HARVARD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 [4 (4' CHLORO 2 BIPHENYLYLMETHYL) 1 PIPERAZINYL] N [4 [3 DIMETHYLAMINO 1 (PHENYLTHIOMETHYL)PROPYLAMINO] 3 NITROBENZENESULFONYL]BENZAMIDE; ABT 263; BH3 PROTEIN; CISPLATIN; ETOPOSIDE; FLT3 PROTEIN INHIBITOR; PACLITAXEL; PROTEIN BAK; PROTEIN BAX; PROTEIN BCL 2; PROTEIN BID; PROTEIN INHIBITOR; UNCLASSIFIED DRUG;

ACUTE GRANULOCYTIC LEUKEMIA; CHRONIC LYMPHATIC LEUKEMIA; DRUG POTENTIATION; DRUG PROTEIN BINDING; FOLLICULAR LYMPHOMA; HUMAN; LUNG NON SMALL CELL CANCER; NEOPLASM; NONHUMAN; PEPTIDE STAPLING; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN MODIFICATION; PROTEIN STRUCTURE; PROTEIN TARGETING; REVIEW;

ANIMALS; ANTINEOPLASTIC AGENTS; DRUG DELIVERY SYSTEMS; DRUG DESIGN; HUMANS; NEOPLASMS; PROTEIN BINDING; PROTEIN STRUCTURE, TERTIARY; PROTO-ONCOGENE PROTEINS C-BCL-2;

EID: 37549040575     PISSN: 10780432     EISSN: None     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-07-2184     Document Type: Review

References (36)

1. Danial NN. BCL-2 family proteins: critical checkpoints of apoptotic cell death. Clin Cancer Res 2007;13:7254-63.
2. Rixe O, Fojo T. Is cell death a critical endpoint for anticancer therapies or is cytostasis sufficient? Clin Cancer Res 2007;13:7280-8.
3. Amaravadi RK, Thompson CB. The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin Cancer Res 2007;13:7271-9.
4. Benz EJ, Jr., Nathan DG. Targeting the cell death-survival equation. Clin Cancer Res 2007;13:7250-3.
5. Hopkins AL, Groom CR. The druggable genome. Nat Rev Drug Discov 2002;1:727-30.
6. Hopkins AL, Groom CR. Target analysis: a priori assessment of druggability. Ernst Schering Res Found Workshop 2003;42:11-7.
7. Russ AP, Lampel S. The druggable genome: an update. Drug Discov Today 2005;10:1607-10.
8. Arkin MR, Wells JA. Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nat Rev Drug Discov 2004;3:301-17.
9. Sattler M, Liang H, Nettesheim D, et al. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science 1997;275:983-6.
10. Petros AM, Nettesheim DG, Wang Y, et al. Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies. Protein Sci 2000;9:2528-34.
11. Liu X, Dai S, Zhu Y, Marrack P, Kappler JW. The structure of a Bcl-xL/Bim fragment complex: implications for Bim function. Immunity 2003;19:341-52.
12. Kvansakul M, van Delft MF, Lee EF, et al. A structural viral mimic of prosurvival Bcl-2: a pivotal role for sequestering proapoptotic Bax and Bak. Mol Cell 2007;25:933-42.
13. Czabotar PE, Lee EF, van Delft MF, et al. Structural insights into the degradation of Mcl-1 induced by BH3 domains. Proc Natl Acad Sci U S A 2007;104:6217-22.
14. Walensky LD, Kung AL, Escher I, et al. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 2004;305:1466-70.
15. Walensky LD, Pitter K, Morash J, et al. A stapled BID BH3 helix directly binds and activates BAX. Mol Cell 2006;24:199-210.
16. Schafmeister CJ, Po J, Verdine GL. An all-hydrocarbon cross-linking system for enhancing the helicity and metabolic stability of peptides. J Am Chem Soc 2000;122:5891-2.
17. Grubbs RH. Olefin metathesis. Tetrahedron 2004;60:7114-40.
18. Wang K, Yin XM, Chao DT, Milliman CL, Korsmeyer SJ. BID: a novel BH3 domain-only death agonist. Genes Dev 1996;10:2859-69.
19. Chen L, Willis SN, Wei A, et al. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 2005;17:393-403.
20. Willis SN, Fletcher JI, Kaufmann T, et al. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 2007;315:856-9.
21. Bernal F, Tyler AF, Korsmeyer SJ, Walensky LD, Verdine GL. Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide. J Am Chem Soc 2006;129:2456-7.
22. Hajduk PJ, Greer J. A decade of fragment-based drug design: strategic advances and lessons learned. Nat Rev Drug Discov 2007;6:211-9.
23. Bartoli S, Fincham CI, Fattori D. Fragment-based drug design: combining philosophy with technology. Curr Opin Drug Discov Devel 2007;10:422-9.
24. Shuker SB, Hajduk PJ, Meadows RP, Fesik SW. Discovering high-affinity ligands for proteins: SAR by NMR. Science 1996;274:1531-4.
25. Petros AM, Dinges J, Augeri DJ, et al. Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis. J Med Chem 2006;49:656-63.
26. Bruncko M, Oost TK, Belli BA, et al. Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J Med Chem 2007;50:641-62.
27. Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005;435:677-81.
28. Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006;10:375-88.
29. Kohl TM, Hellinger C, Ahmed F, et al. BH3 mimetic ABT-737 neutralizes resistance to FLT3 inhibitor treatment mediated by FLT3-independent expression of BCL2 in primary AML blasts. Leukemia 2007;21:1763-72.
30. van Delft MF, Wei AH, Mason KD, et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1is neutralized. Cancer Cell 2006;10:389-99.
31. Muchmore SW, Sattler M, Liang H, et al. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 1996;381:335-41.
32. Walensky LD. BCL-2 in the crosshairs: tipping the balance of life and death. Cell Death Differ 2006;13:1339-50.
33. Nagar B, Bornmann WG, Pellicena P, et al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res 2002;62:4236-43.
34. Cho HS, Mason K, Ramyar KX, et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 2003;421:756-60.
35. Manion MK, O'Neill JW, Giedt CD, Kim KM, Zhang KY, Hockenbery DM. Bcl-XL mutations suppress cellular sensitivity to antimycin A. J Biol Chem 2004;279:2159-65.
36. Lee EF, Czabotar PE, Smith BJ, et al. Crystal structure of ABT-737 complexed with Bcl-x(L): implications for selectivity of antagonists of the Bcl-2 family. Cell Death Differ 2007;14:1711-3.