| Autor: |
Tarr, James C., Salovich, James M., Aichinger, Martin, Jeon, KyuOk, Veerasamy, Nagarathanam, Sensintaffar, John L., Arnhof, Heribert, Samwer, Matthias, Christov, Plamen P., Kim, Kwangho, Wunberg, Tobias, Schweifer, Norbert, Trapani, Francesca, Arnold, Allison, Martin, Florian, Zhao, Bin, Miriyala, Nagaraju, Sgubin, Danielle, Fogarty, Stuart, Moore, William J., Stott, Gordon M., Olejniczak, Edward T., Engelhardt, Harald, Rudolph, Dorothea, Lee, Taekyu, McConnell, Darryl B., Fesik, Stephen W. |
| Zdroj: |
Journal of Medicinal Chemistry; 20240101, Issue: Preprints |
| Abstrakt: |
Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 inhibitor, compound 26, that binds to Mcl-1 with subnanomolar affinity, inhibits growth in cell culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments. Evaluation of 26as a single agent in Mcl-1 sensitive hematological and solid tumor xenograft models resulted in regressions. Co-treatment of Mcl-1-sensitive and Mcl-1 insensitive lung cancer derived xenografts with 26and docetaxel or topotecan, respectively, resulted in an enhanced tumor response. These findings support the premise that pro-apoptotic priming of tumor cells by other therapies in combination with Mcl-1 inhibition may significantly expand the subset of cancers in which Mcl-1 inhibitors may prove beneficial. |
| Databáze: |
Supplemental Index |
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