Bad news for cancer. The Bcl-2 (B-cell lymphoma 2) family of proteins is comprised of both pro-apoptotic and anti-apoptotic members that operate through a complex series of protein-protein interactions [1-3]. The pro-apoptotic proteins are categorized into two groups based on the number of Bcl homology (BH) domains: 1) those with 3 BH domains (BH1-BH3 such as Bax and Bak) and 2) those with a single BH domain (BH-3 only such as Bad, Bik, Puma, etc...). The prosurvival (anti-apoptotic) members contain four BH domains (BH1-BH4 such as Bcl-2, Bcl-xL, etc...). Overexpression of Bcl-2 and its closely related counterpart Bcl-xL affords a mechanism by which cancer cells suppress apoptotic signaling, confer a survival advantage and provide resistance to chemotherapy [1-3]. Recognizing that inhibition of Bcl-2 family members should specifically target the abnormal cell death pathway in the overexpressing cancer cells led Elmore and co-workers at Abbott labs to launch a drug discovery campaign aimed at developing small molecule protein-protein inhibitors of the Bcl-2 family [4-6]. Initial work centered on a class of potent biarylacylsulfonamide antagonists - outside the usual α-helical mimetics - and a lead compound which bound Bcl-xL with a Ki of 800 pM . Despite effective cytotoxic activity with multiple cytotoxic agents and UV irradiation, this Bcl-xL antagonist had no single agent efficacy across a large panel of human tumor cell lines. Elmore and co-workers then reasoned that since this inhibitor was developed by structure-based design aimed at Bcl-xL, it was not surprising that it exhibited much lower affinity for Bcl-2 [5,6]. Since Bcl-2 overexpression is a major hallmark of many human cancers, the team sought to broaden their inhibitor profile to target both Bcl-xL and Bcl-2; interestingly, despite only 49% homology, the three-dimensional structures of Bcl-xL and Bcl-2 are similar. The researchers focused in on the largest structural distinction between the two - a different helical fold of the α3 helix . The α3 helix borders one side of the hydrophobic binding groove, and there exists a wider groove for Bcl-2 than Bcl-xL and a deeper hydrophobic pocket within the groove for Bcl-2 than Bcl-xL. Based on this key structural difference, the team designed modified inhibitors to access this deep hydrophobic pocket in the floor of the groove and thereby increasing affinity for Bcl-2. Their strategy worked! A chemical lead optimization campaign along with structure-guided design resulted in the identification of a clincal candidate, ABT-737, the first dual, subnanomolar inhibitors of Bcl- 2 and Bcl-xL (Ki < 1 nM and < 0.5 nM, respectively) and with EC50s of 8 nM and 30 nM, respectively . ABT-737 showed single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2 and efficacy in a murine tumor xenograft model of lymphoma when given as either a single agent or in combination with etoposide. ABT-737 was also efficacious in two mice small cell lung carcinoma xenograft models known to be resistant to most cytotoxic agents. For example, ABT-737 administered i.p. at 75 mg/kg/day for 21 days in a H146 model caused complete regression of established xenografts and 58 days after cessation of therapy, the tumors did not grow back in 77% of the mice [5,6]. ABT-737 represents a significant advance in the discovery and development of small molecule protein-protein inhibitors and clinical data in human patients is eagerly awaited. REFERENCES  Cory, S.; Adams, J.M. The Bcl2 family: regulators of the cellular life-ordeath switch. Nat. Rev. Cancer 2002, 2, 647-656.  Borner, C. The Bcl2 protein family: sensor and checkpoints for life-or-death decisions. Mol. Immunol. 2003, 39, 615-647.  van Delft, M.F.; Huang, D.S.C. How the Bcl-2 family of proteins interact to regulate apoptosis. Cell. Res. 2006, 16, 203-213.  Wendt, M.D.; Shen, W.; Kunzer, A.; McClellan, W.J.; Bruncko, M.; Oost, T.K.; Ding, H.; Joseph, M. K.; Zhang, H.; Nimmer, P.M.; Ng, S.-C.; Shoemaker, A.R.; Petros, A.M.; Oleksijew, A.; Marsh, K.; Bauch, J.; Oltersdorf, T.; Belli, B.A.; Martineau, D.; Fesik, S.W.; Rosenberg, S. H.; Elmore, S.W. Discovery and structure-activity relationship of antagonists of B-Cell Lymphoma 2 Family Proteins with chemopotentiation activity in vitro and in vivo. J. Med. Chem. 2006, 49, 1165-1181.