| Autor: |
Ma, Xiaoshen, Sloman, David L., Duggal, Ruchia, Anderson, Kenneth D., Ballard, Jeanine E., Bharathan, Indu, Brynczka, Christopher, Gathiaka, Symon, Henderson, Timothy J., Lyons, Thomas W., Miller, Richard, Munsell, Erik V., Orth, Peter, Otte, Ryan D., Palani, Anandan, Rankic, Danica A., Robinson, Michelle R., Sather, Aaron C., Solban, Nicolas, Song, Xuelei Sherry, Wen, Xin, Xu, Zangwei, Yang, Yi, Yang, Ruojing, Day, Phil J., Stoeck, Alexander, Bennett, David Jonathan, Han, Yongxin |
| Zdroj: |
Journal of Medicinal Chemistry; 20240101, Issue: Preprints |
| Abstrakt: |
Oncogenic mutations in the RASgene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously “undruggable” target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRASG12Ccovalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability. |
| Databáze: |
Supplemental Index |
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