Targeting Key Regulatory Proteins in Apoptotic Pathways

Selective targeting of certain protein-protein interactions in apoptosis pathways has been pursued as a new therapeutic approach to the treatment of cancers and other diseases that stem from the dysregulation of the apoptosis process. Ascentage is at the forefront of the discovery and development of small molecule therapeutics targeting PPIs in apoptosis pathways. We are the only company with active clinical programs targeting all three known classes of key apoptosis regulators. Specifically, our pipeline includes three clinical compounds targeting the Bcl-2 family of proteins: APG-1252 for SCLC, other solid tumors and lymphoma; APG-2575 for B-cell malignancies; and AT-101 for chronic lymphocytic leukemia. Two other apoptosis-targeting candidates include APG-1387 (a pan-IAP inhibitor) and APG-115 (an MDM2-p53 inhibitor). We are also evaluating APG-1387 in China for HBV. The mechanisms of these compounds are depicted in the illustration below:

  1. BCL-2 Pathway: APG-1252 (Bcl-2/Bcl-xL dual inhibitor) or APG-2575 (Bcl-2 selective inhibitor) can compete for the binding of pro-death proteins with Bcl-2 or Bcl-xL (dual inhibitor only), thus triggering the downstream cascade of BAX/BAK oligomerization, cytochrome c (Cyt c)/SMAC release from mitochondria and caspase activation, leading to cancer cell death (apoptosis). AT-101 is a pan Bcl-2, Bcl-xL and Mcl-1 inhibitor which can neutralize the anti-apoptotic function of these proteins and trigger the downstream cascade of BAX/BAK oligomerization, Cyt c/SMAC release from mitochondria and caspase activation, leading to cancer cell death (apoptosis).
  2. IAP Pathway: APG-1387 is a SMAC mimetic which can antagonize the function of cIAP or XIAP, which triggers caspase activation and leads to apoptosis.
  3. MDM2-p53 Pathway: APG-115 is a second generation MDM2 inhibitor that can block the interaction of MDM2-p53, thus stabilizing the p53 protein and allowing it to resume its transcriptional regulation function for the cell cycle and apoptosis.