Novel Mcl-1 His and Lys covalent agents from a fragment-merging approach

Antiapoptotic Mcl-1 is overexpressed in cancer and cancer-associated fibroblasts. Clinical development of Mcl-1 inhibitors has been hampered by on-target cardiotoxicity. We propose novel covalent Mcl-1 chemotypes targeting binding site Lys or His residues, designed using covalent-fragment merging strategies. We envision deploying our agents to restore sensitivity to immunotherapy or chemotherapy, for the treatment of peritoneal metastases. The intraperitoneal delivery route would limit systemic circulation of the drug and cardiac toxicity.