Design, Synthesis and Biological Evaluation of Non-Peptidic Small Molecular SMAC Mimetics as Potent IAP Inhibitors.

[摘要] The resistance of tumor cells to apoptosis is a major problem in current cancer therapies. Successful anticancer strategies would benefit from specific targeting of the pathways that cause the resistance. Hence, targeting the crucial negative regulators that play a role in inhibition of apoptosis in cancer cells might be a promising therapeutic strategy.IAPs (Inhibitors of Apoptosis Protein) are a class of proteins which can negatively regulate the apoptosis process in cancer cells. Among eight human IAPs, XIAP (X-chromosome linked IAP) is most potent IAP member through its actions on both caspase-9, mediated by its BIR (Baculovirus IAP Repeat) 3 domain, and caspase-3/7 via its linker region between BIR 1 and BIR 2. By blocking caspases, the central executioners of programmed cell death, XIAP inhibits apoptosis in tumor cells. Smac (Second Mitochondria-derived Activator of Caspase), released from mitochondria, is an endogenous inhibitor of XIAP, c-IAP1 (cellular IAP 1), and c-IAP2 (cellular IAP 2). The amino-terminal tetrapeptide Ala-Val-Pro-Ile of mature Smac protein binds to a well-defined surface groove in the BIR 3 domain of XIAP. Moreover, Smac proteins can form a homodimer, interacting with both XIAP BIR 3 and BIR 2 domains to release both initiator and effector caspases to promote apoptosis.In the work presented here, a series of monvalent and bivalent Smac mimetics were designed and synthesized in this dissertation, based on the amino-terminal tetrapeptide of Smac. Both types of Smac mimetics show high binding affinities to XIAP, c-IAP1/2. These Smac mimetics also show excellent activity against tumor cells, both inducing apoptosis and inhibiting cell growth. The cellular activities of bivalent Smac mimetics are 100 to 1000 times more potent than their corresponding monovalent Smac variants.Further modifications of monovalent Smac mimetics led to the discovery of SM-406 as a promising drug candidate. Extensive studies have been carried out to investigate the cellular mechanism of action of SM-406 in apoptosis induction in cancer cells. The studies show that SM-406 induces rapid degradation of c-IAP1 but not XIAP, and its activity depends on caspase-8 and caspase-3 and partially on caspase-9. Caspase-8 activation caused by c-IAP1 degradation leads to apoptosis.

[发布机构] University of Michigan

[效力级别] XIAP

[关键词] Smac;XIAP;C-IAP1;C-IAP2;Apoptosis;Cancer;Chemistry;Oncology and Hematology;Pharmacy and Pharmacology;Science (General);Health Sciences;Science;Medicinal Chemistry