Protein-Protein Interactions

Targeting Key Regulatory Proteins
in Apoptotic Pathways

Selective targeting of certain protein-protein interactions (PPI) 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, a global clinical-stage biotechnology company, is at the forefront of the discovery and development of small molecule therapeutics targeting PPIs in apoptosis pathways. We are the only company targeting all 3 intrinsic apoptotic pathways: Bcl-2, IAP, MDM2-p53. Specifically, our pipeline includes 3 clinical compounds targeting the Bcl-2 family of proteins: APG-1252 for SCLC/NSCLC, lymphoma and other solid tumors; APG-2575 for leukemia, WM and other blood cancers; and AT-101 for CLL. 2 other apoptosis-targeting candidates include APG-1387 (a pan-IAP inhibitor) for Hepatitis B and solid tumors; APG-115 (a MDM2-p53 inhibitor) for AML and solid tumors.

 
  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.