8XJJ
Co-crystal structure of SOS-1 and a potent, selective and orally bioavailable SOS1 inhibitor RGT-018
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Summary for 8XJJ
| Entry DOI | 10.2210/pdb8xjj/pdb |
| Descriptor | Son of sevenless homolog 1, 5-[4-[[(1~{R})-1-[3-[bis(fluoranyl)methyl]-2-fluoranyl-phenyl]ethyl]amino]-2-methyl-6-morpholin-4-yl-7-oxidanylidene-pyrido[4,3-d]pyrimidin-8-yl]pyridine-2-carbonitrile, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | sos1, selective inhibitor, kras-driven cancers, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 69265.62 |
| Authors | |
| Primary citation | Xiao, F.,Wang, K.,Wang, X.,Li, H.,Hu, Z.,Ren, X.,Huang, W.,Feng, T.,Yao, L.,Lin, J.,Li, C.,Zhang, Z.,Mei, L.,Zhu, X.,Zhong, W.,Xie, Z. Discovery of RGT-018: A Potent, Selective, and Orally Bioavailable SOS1 Inhibitor for KRAS-Driven Cancers. Mol.Cancer Ther., 23:1703-1716, 2024 Cited by PubMed Abstract: KRAS is the most frequently dysregulated oncogene with high prevalence in NSCLC, colorectal cancer, and pancreatic cancer. FDA-approved sotorasib and adagrasib provide breakthrough therapies for cancer patients with KRASG12C mutation. However, there is still high unmet medical need for new agents targeting broader KRAS-driven tumors. An emerging and promising opportunity is to develop a pan KRAS inhibitor by suppressing the upstream protein SOS1. SOS1 is a key activator of KRAS and facilitates the conversion of GDP-bound KRAS state to GTP-bound KRAS state. Binding to its catalytic domain, small molecule SOS1 inhibitor has demonstrated the ability to suppress KRAS activation and cancer cell proliferation. RGT-018, a potent and selective SOS1 inhibitor, was identified with optimal drug-like properties. In vitro, RGT-018 blocked the interaction of KRAS:SOS1 with single digit nM potency and is highly selective against SOS2. RGT-018 inhibited KRAS signaling and the proliferation of a broad spectrum of KRAS-driven cancer cells as a single agent in vitro. Further enhanced anti-proliferation activity was observed when RGT-018 was combined with MEK, KRASG12C, EGFR or CDK4/6 inhibitors. Oral administration of RGT-018 inhibited tumor growth and suppressed KRAS signaling in tumor xenografts in vivo. Combination with MEK or KRASG12C inhibitors led to significant tumor regression. Furthermore, RGT-018 overcame the resistance to the approved KRASG12C inhibitors caused by clinically acquired KRAS mutations either as a single agent or in combination. RGT-018 displayed promising pharmacological properties for combination with targeted agents to treat a broader KRAS-driven patient population. PubMed: 39087485DOI: 10.1158/1535-7163.MCT-24-0049 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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