Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Abbott JR

PROVIDER: S-EPMC6142059 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Abbott Jason R JR Patel Pratiq A PA Howes Jennifer E JE Akan Denis T DT Kennedy J Phillip JP Burns Michael C MC Browning Carrie F CF Sun Qi Q Rossanese Olivia W OW Phan Jason J Waterson Alex G AG Fesik Stephen W SW

ACS medicinal chemistry letters 20180808 9

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 ...[more]

PMID: 30258545

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Project description:Macrophages are important immune sentinels that detect and clear pathogens and initiate inflammatory responses through the activation of surface receptors, including Toll-like receptors (TLRs). Activated TLRs employ complex cellular trafficking and signalling pathways to initiate transcription for inflammatory cytokine programs. We have previously shown that Rab8a is activated by multiple TLRs and regulates downstream Akt/mTOR signalling by recruiting the effector PI3Kγ, but the guanine nucleotide exchange factors (GEF) canonically required for Rab8a activation in TLR pathways is not known. Using GST affinity pull-downs and mass spectrometry analysis, we identified a Rab8 specific GEF, GRAB, as a Rab8a binding partner in LPS-activated macrophages. Co-immunoprecipitation and fluorescence microscopy showed that both GRAB and a structurally similar GEF, Rabin8, undergo LPS-inducible binding to Rab8a and are localised on cell surface ruffles and macropinosomes where they coincide with sites of Rab8a mediated signalling. Rab nucleotide activation assays with CRISPR-Cas9 mediated knock-out (KO) cell lines of GRAB, Rabin8 and double KOs showed that both GEFs contribute to TLR4 induced Rab8a GTP loading, but not membrane recruitment. In addition, measurement of signalling profiles and live cell imaging with the double KOs revealed that either GEF is individually sufficient to mediate PI3Kγ-dependent Akt/mTOR signalling at macropinosomes during TLR4-driven inflammation, suggesting a redundant relationship between these proteins. Thus, both GRAB and Rabin8 are revealed as key positive regulators of Rab8a nucleotide exchange for TLR signalling and inflammatory programs. These GEFs may be useful as potential targets for manipulating inflammation. Abbreviations: TLR: Toll-like Receptor; OCRL: oculocerebrorenal syndrome of Lowe protein; PI3Kγ: phosphoinositol-3-kinase gamma; LPS: lipopolysaccharide; GEF: guanine nucleotide exchange factor; GST: glutathione S-transferases; BMMs: bone marrow derived macrophages; PH: pleckstrin homology; GAP: GTPase activating protein; ABCA1: ATP binding cassette subfamily A member 1; GDI: GDP dissociation inhibitor; LRP1: low density lipoprotein receptor-related protein 1.

Dataset Information

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

Publications

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

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