Target Validation Information
Target ID T31309
Target Name Apoptosis regulator Bcl-2
Target Type
Successful
Drug Potency against Target TW-37 Drug Info IC50 = 200 nM [528469]
4,5-dibenzylbenzene-1,2-diol Drug Info IC50 = 4700 nM [530890]
5,10-Dioxy-2-phenyl-benzo[g]pteridin-4-ylamine Drug Info IC50 = 1600 nM [526209]
ABT-263 Drug Info Ki = 0.5 nM [552892]
MCI-186 Drug Info IC50 = 270 nM [552460]
ABT-737 Drug Info Ki < 1 nM [528642]
2,3,4-trihydroxy-5-isopropyl-N-phenyl-benzamide Drug Info IC50 = 7000 nM [528469]
N-phenyl-2,3,4-trihydroxy-5-benzyl-benzamide Drug Info IC50 = 5000 nM [528469]
QEDIIRNIARHLAQVGDSMDR Drug Info Ki = 11 nM [528469]
The Effect of Target Knockout, Knockdown or Genetic Variations Bcl-2(-/-) mice are growth-retarded and exhibit increased bone vol uMe of the primary spongiosa, mainly due to the decreased n uMber and dysfunction of osteoclasts. Osteoblast function is also impaired in Bcl-2(-/-) mice. Ex vivo studies on osteoblasts and osteoclasts showed that Bcl-2 promoted the differentiation, activation, and survival of both cell types. Because Bcl-2(-/-) mice die before 6 weeks of age due to renal failure and cannot be compared with adult wild type mice, we generated Bcl-2(-/-)Bim(+/-) mice, in which a single Bim allele was inactivated, and compared them with their Bcl-2(+/-)Bim(+/-) littermates. Loss of a single Bim allele restored normal osteoclast function in Bcl-2(-/-) mice but did not restore the impaired function of osteoblasts, and the mice exhibited osteopenia. These data demonstrate that Bcl-2 promotes the differentiation, activity, and survival of both osteoblasts and osteoclasts. The balance between Bcl-2 and Bim regulates osteoclast apoptosis and function, whereas other pro-apoptotic members are important for osteoblasts. [528469]
References
Ref 528469J Med Chem. 2006 Oct 19;49(21):6139-42.Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins.
Ref 530890J Med Chem. 2010 May 27;53(10):3899-906.Vaccinia virus virulence factor N1L is a novel promising target for antiviral therapeutic intervention.
Ref 526209J Med Chem. 2001 Dec 6;44(25):4313-24.Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening.
Ref 552892BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov. 2008 Dec;7(12):989-1000. doi: 10.1038/nrd2658.
Ref 552460A newly synthesized poly(ADP-ribose) polymerase inhibitor, DR2313 [2-methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]-pyrimidine-4-one]: pharmacological profiles, neuroprotective effects, and therapeutic time window in cerebral ischemia in rats. J Pharmacol Exp Ther. 2005 Feb;312(2):472-81. Epub 2004 Oct 1.
Ref 528642J Med Chem. 2007 Feb 22;50(4):641-62. Epub 2007 Jan 26.Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL.
Ref 528469J Med Chem. 2006 Oct 19;49(21):6139-42.Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins.
Ref 528469J Med Chem. 2006 Oct 19;49(21):6139-42.Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins.
Ref 528469J Med Chem. 2006 Oct 19;49(21):6139-42.Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins.

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