Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS.

Autor:	Abbott JR; Department of Biochemistry and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Patel PA; Department of Biochemistry and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Howes JE; Department of Biochemistry and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Akan DT; Department of Biochemistry and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Kennedy JP; Department of Biochemistry and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Burns MC; Department of Biochemistry and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Browning CF; Department of Biochemistry and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Sun Q; Department of Biochemistry and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Rossanese OW; Department of Biochemistry and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Phan J; Department of Biochemistry and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Waterson AG; Department of Biochemistry and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States.; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232-0146, United States., Fesik SW; Department of Biochemistry and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States.; Department of Biochemistry and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States.; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232-0146, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2018 Aug 08; Vol. 9 (9), pp. 941-946. Date of Electronic Publication: 2018 Aug 08 (Print Publication: 2018).
DOI:	10.1021/acsmedchemlett.8b00296
Abstrakt:	Proteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over the last 30 years, RAS proteins have proven to be recalcitrant therapeutic targets. One approach for modulating RAS signaling is to target proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report hit-to-lead studies on quinazoline-containing compounds that bind to SOS1 and activate nucleotide exchange on RAS. Using structure-based design, we refined the substituents attached to the quinazoline nucleus and built in additional interactions not present in the initial HTS hit. Optimized compounds activate nucleotide exchange at single-digit micromolar concentrations in vitro. In HeLa cells, these quinazolines increase the levels of RAS-GTP and cause signaling changes in the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway. Competing Interests: The authors declare the following competing financial interest(s): RAS activator compounds have been licensed to Boehringer Ingelheim.
Databáze:	MEDLINE
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