Reference Detail

Ref Type

Journal Article

PMID

(39087485)

Authors

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

Title

Discovery of RGT-018: a Potent, Selective and Orally Bioavailable SOS1 Inhibitor for KRAS-driven Cancers.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics			2024 Aug 01		Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
RGT-018	RGT-018	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
RGT-018		RGT 018\|RGT018	SOS1 Inhibitor 16	RGT-018 selectively inhibits SOS1, potentially resulting in decreased tumor cell proliferation and reduced tumor growth (PMID: 39087485).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	melanoma	no benefit	RGT-018	Preclinical - Cell culture	Actionable	In a preclinical study, RGT-018 did not inhibit proliferation of melanoma cells harboring BRAF V600E in 3D culture (PMID: 39087485).	39087485