1. Discovery of an Oral, Beyond-Rule-of-Five Mcl-1 Protein-Protein Interaction Modulator with the Potential of Treating Hematological Malignancies.
- Author
-
Romanov-Michailidis F, Hsiao CC, Urner LM, Jerhaoui S, Surkyn M, Miller B, Vos A, Dominguez Blanco M, Bueters R, Vinken P, Bekkers M, Walker D, Pietrak B, Eyckmans W, Dores-Sousa JL, Joo Koo S, Lento W, Bauser M, Philippar U, and Rombouts FJR
- Subjects
- Humans, Mice, Animals, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Cell Line, Tumor, Apoptosis, Proto-Oncogene Proteins c-bcl-2 metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Antineoplastic Agents chemistry, Hematologic Neoplasms drug therapy
- Abstract
Avoidance of apoptosis is critical for the development and sustained growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family of proteins which is overexpressed in many cancers. Upregulation of Mcl-1 in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Therefore, pharmacological inhibition of Mcl-1 is regarded as an attractive approach to treating relapsed or refractory malignancies. Herein, we disclose the design, synthesis, optimization, and early preclinical evaluation of a potent and selective small-molecule inhibitor of Mcl-1. Our exploratory design tactics focused on structural modifications which improve the potency and physicochemical properties of the inhibitor while minimizing the risk of functional cardiotoxicity. Despite being in the "non-Lipinski" beyond-Rule-of-Five property space, the developed compound benefits from exquisite oral bioavailability in vivo and induces potent pharmacodynamic inhibition of Mcl-1 in a mouse xenograft model.
- Published
- 2023
- Full Text
- View/download PDF