1、OutlineBackgroundl Hallmarks of Cancerl The Bcl-2 Protein FamilyModel of BH3 mimetic-induced apoptosisStructure basis for designing ligandsSmall molecule inhibitorsl Peptidomimetic approach mimic the a-helix of the BH3 peptidesl ABT-737, ABT-263 and their analogsl pan-active inhibitor of Bcl-2l Sele
2、ctive Bcl-2 inhibitorsl selective BCL-xL inhibitorl Selective Mcl-1 inhibitors1,Cell,144(5): 646-674Hallmarks of Cancer 2Extrinsic and intrinsic pathways of apoptosisExpert Opin. Ther. Patents (2012) ,22(1):37-553The Bcl-2 Protein FamilyThe Bcl-2 Family Proteins with anti- or pro-apoptotic function
3、Characteristics: (Often) a C-terminal transmembrane domain. Bcl-2 homology (BH) domains. Bcl-2 proteins form homo- and heterodimers via their BH-domains BH1, BH2: Predicted to form ion channels BH3: The ”suicide domain” regulates cell death BH4: Thought to confer anti-apoptotic activity.(Chan & Yu.
4、(2004). Clin. Exp. Pharmacol. Physiol. 31: 119).Chipuk, J. E， Molecular Cell ， 2010， 37(3): 299-3104Elevated of Bcl-2 or Bcl-xL expressionSeminars in Oncology, 2004,30(Supplement 16): 133-142.5Model of BH3 mimetic-induced apoptosis一、直接模型：抑制剂代替促凋亡蛋白 BAK/BAX，与抗凋亡蛋白 Bcl-2/Bcl-xl结合，从而抑制后者，促进细胞凋亡二、间接模型抑制
5、剂替代特定的激活因子 BH3-only蛋白，与抗调亡蛋白如 BCL-2/BCL-xL结合，游离出来的 BH3-only蛋白，激活 BAK/BAX。Nature Reviews Drug Discovery 2008， 7(12): 989-1000Clinical Cancer Research 2009， 15(4): 1126-1132.Oncogene ， 2009， 27(S1): S149-S157.6Structure basis for designing ligands7The molecular basis for heterodimer formation Heterodi
6、merization between members of the Bcl-2 family of proteins is a key event in the regulation of apoptosis pro-apoptotic protein(Bak) adopts an amphipathic a- helix(BH3 domain) that interacts with anti-apoptotic proteins(Bcl-xl) through hydrophobic and electrostatic interactions in the hydrophobic cle
7、ft. 8抗凋亡蛋白 (BCL-2)是通过其表面疏水凹槽与促凋亡类(BIM)的 BH3区域结合发生相互作用，调节细胞正常的生理凋亡 。BCL-2 family antagonists for cancer therapy. Nature Reviews Drug Discovery 2008， 7(12): 989-1000Overlay of BCL-XLABT-737 complex with BCL-xlLBIM BH3 complexBcl-2 and BIM BH3 9Bcl-xL and Bak-BH3 Surface representation of the binding pocket of Bcl-xL bound to the Bak peptide10. “Structure of Bcl-xL-Bak Peptide Complex: Recognition Between Regulators of Apoptosis.“ Science 1997， 275(5302): 983-986.
