2022
DOI: 10.1158/1538-7445.am2022-6368
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Abstract 6368: Discovery of potent, orally bioavailable, SOS1 inhibitors for KRAS-driven tumors

Abstract: KRAS is an oncogene implicated in a wide variety of tumors (~21% of solid tumors harbor KRAS mutations). KRAS interaction with Guanidine Exchange Factors (GEFs) is crucial for its activation, with SOS1 being the predominant GEF. SOS1 inhibition is thus expected to be an effective strategy for targeting the downstream signaling pathway, resulting in anti-proliferative activity in RAS-driven cancers. We have identified multiple potent and selective SOS1 inhibitors, demonstrating significant reduction of GEF acti… Show more

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“…Complete regioselectivity for substitution of the C5-triflate was observed in all cases, and the C7-amino substituted naphthyridine was not observed or isolated in any case. This is consistent with literature precedent for substitution of similar heterocycles and we hypothesize that the steric occlusion of C7 by the group at C8 further biases the reaction toward substitution of the C5 triflate. ,,, …”
Section: Resultsmentioning
confidence: 99%
“…Complete regioselectivity for substitution of the C5-triflate was observed in all cases, and the C7-amino substituted naphthyridine was not observed or isolated in any case. This is consistent with literature precedent for substitution of similar heterocycles and we hypothesize that the steric occlusion of C7 by the group at C8 further biases the reaction toward substitution of the C5 triflate. ,,, …”
Section: Resultsmentioning
confidence: 99%