Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor
| Autor: | Jeff Kucharski, Ulf Peters, Yun O. Long, Shisheng Li, Pingda Ren, Ata Zarieh, Dana D. Hu-Lowe, Ke Yu, Yuan Liu, Tao Wu, Carol Thach, Dirk Brehmer, Tess Ely, Xin Guo, Patrick P. Zarrinkar, Matthew P. Patricelli, Yi Wang, Rasmus Hansen, Dashyant Dhanak, Yi Liu, Jun Feng, Shuangwei Li, Matthew R. Janes, Yuching Chen, Sarah J. Firdaus, Levan Darjania, Linda Kessler, Jeffrey H. Chen, Xiaohu Deng, Yvonne Yao, Anjali Babbar, Matthew V. Lorenzi, Jingchuan Zhang, Lian-Sheng Li |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Mutant Allosteric regulation Druggability Mice Nude Antineoplastic Agents Plasma protein binding Biology medicine.disease_cause Piperazines General Biochemistry Genetics and Molecular Biology Proto-Oncogene Proteins p21(ras) Mice 03 medical and health sciences medicine Animals Humans Cells Cultured Cell Proliferation Mice Inbred BALB C Mutation Oncogene HEK 293 cells Neoplasms Experimental HCT116 Cells Molecular Docking Simulation HEK293 Cells 030104 developmental biology Quinazolines Cancer research Female KRAS Protein Binding |
| Zdroj: | Cell. 172:578-589.e17 |
| ISSN: | 0092-8674 |
| Popis: | KRASG12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRASG12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRASG12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRASG12C-specific inhibitors with promising therapeutic potential. |
| Databáze: | OpenAIRE |
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