Reference Detail

Ref Type

Journal Article

PMID

(38224565)

Authors

Begovich K, Schoolmeesters A, Rajapakse N, Martinez-Terroba E, Kumar M, Shakya A, Lai C, Greene S, Whitefield B, Okano A, Mali V, Huang S, Chourasia AH, Fung L

Title

Cereblon-based Bifunctional Degrader of SOS1, BTX-6654, Targets Multiple KRAS Mutations and Inhibits Tumor Growth.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	23	4	2024 Apr 02	407-420	Mol Cancer Ther

URL

Abstract Text

Mutations within the oncogene KRAS drive an estimated 25% of all cancers. Only allele-specific KRAS G12C inhibitors are currently available and are associated with the emergence of acquired resistance, partly due to upstream pathway reactivation. Given its upstream role in the activation of KRAS, son of sevenless homolog 1 (SOS1), has emerged as an attractive therapeutic target. Agents that target SOS1 for degradation could represent a potential pan-KRAS modality that may be capable of circumventing certain acquired resistance mechanisms. Here, we report the development of two SOS1 cereblon-based bifunctional degraders, BTX-6654 and BTX-7312, cereblon-based bifunctional SOS1 degraders. Both compounds exhibited potent target-dependent and -specific SOS1 degradation. BTX-6654 and BTX-7312 reduced downstream signaling markers, pERK and pS6, and displayed antiproliferative activity in cells harboring various KRAS mutations. In two KRAS G12C xenograft models, BTX-6654 degraded SOS1 in a dose-dependent manner correlating with tumor growth inhibition, additionally exhibiting synergy with KRAS and MEK inhibitors. Altogether, BTX-6654 provided preclinical proof of concept for single-agent and combination use of bifunctional SOS1 degraders in KRAS-driven cancers.

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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
BTX-6654	BTX-6654	1	0
BTX-7312	BTX-7312	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
BTX-6654		BTX6654\|BTX 6654	SOS1 Inhibitor 16	BTX-6654 is a bifunctional SOS1 degrader that potentially decreases downstream KRAS signaling and inhibits tumor growth (PMID: 38224565).
BTX-7312		BTX7312\|BTX 7312	SOS1 Inhibitor 16	BTX-7312 is a bifunctional SOS1 degrader that potentially decreases downstream KRAS signaling and inhibits tumor growth (PMID: 38224565).

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
HRAS Q61H	uterine cancer	sensitive	BTX-6654	Preclinical - Cell culture	Actionable	In a preclinical study, BTX-6654 inhibited proliferation of a uterine cancer cell line harboring HRAS Q61H in 3D culture (PMID: 38224565).	38224565
HRAS Q61H	uterine cancer	sensitive	BTX-7312	Preclinical - Cell culture	Actionable	In a preclinical study, BTX-7312 inhibited proliferation of a uterine cancer cell line harboring HRAS Q61H in 3D culture (PMID: 38224565).	38224565