Myeloid cell leukemia 1 (Mcl-1)， an antiapoptotic member of the Bcl-2 family of proteins， has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade， poor survival， and resistance to chemotherapy. Here， we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy， including growth inhibition and caspase induction in Mcl-1-sensitive cells. Thus， they represent useful compounds to study the implication of Mcl-1 inhibition in cancer and serve as potentially useful starting points toward the discovery of anti-Mcl-1 therapeutics.