Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling

Abbott, Jason R.; Hodges, Timothy R.; Daniels, R. Nathan; Patel, Phenil J.; Kennedy, J. Phillip; Howes, Jennifer E.; Akan, Denis T.; Burns, Michael C.; Sai, Jiqing; Sobolik, Tammy; Beesetty, Yugandhar; Lee, T; Rossanese, Olivia W.; Phan, Jason; Waterson, Alex G.; Fesik, Stephen W.

doi:10.1021/acs.jmedchem.8b00360

Cited by 32 publications

(54 citation statements)

References 39 publications

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“…Rasarfin inhibits Ras, ARF6, and cell proliferation in cancer cells. Because Ras proteins are key regulators of normal cell proliferation and survival, inhibitors of this small G protein have been developed for the treatment of cancers [46][47][48] . We, therefore, assessed Rasarfin's effects on cancer cells viability and proliferation.…”

Section: Sar Studies On Rasarfin Identify Functionally Selective Analogsmentioning

confidence: 99%

Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen

et al. 2021

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Internalization and intracellular trafficking of G protein-coupled receptors (GPCRs) play pivotal roles in cell responsiveness. Dysregulation in receptor trafficking can lead to aberrant signaling and cell behavior. Here, using an endosomal BRET-based assay in a high-throughput screen with the prototypical GPCR angiotensin II type 1 receptor (AT1R), we sought to identify receptor trafficking inhibitors from a library of ~115,000 small molecules. We identified a novel dual Ras and ARF6 inhibitor, which we named Rasarfin, that blocks agonist-mediated internalization of AT1R and other GPCRs. Rasarfin also potently inhibits agonist-induced ERK1/2 signaling by GPCRs, and MAPK and Akt signaling by EGFR, as well as prevents cancer cell proliferation. In silico modeling and in vitro studies reveal a unique binding modality of Rasarfin within the SOS-binding domain of Ras. Our findings unveil a class of dual small G protein inhibitors for receptor trafficking and signaling, useful for the inhibition of oncogenic cellular responses.

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Section: Sar Studies On Rasarfin Identify Functionally Selective Analogsmentioning

confidence: 99%

Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen

et al. 2021

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“…The ability of these compounds to affect SOS1-mediated nucleotide exchange was assessed by using a high-throughput nucleotide exchange assay (Burns et al, 2014Abbott et al, 2018). Data analysis showed that compound 34 (Figure 7) had an EM50 (in vitro compound potency was defined as the half maximal effective concentration .)…”

Section: Inhibition Of Sos-mediated Activationmentioning

confidence: 99%

Regulation of the Ras-Related Signaling Pathway by Small Molecules Containing an Indole Core Scaffold: A Potential Antitumor Therapy

Chen

Zhu

et al. 2020

Front. Pharmacol.

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The Ras-Related signaling pathway plays an important role in cell development and differentiation. A growing body of evidence collected in recent years has shown that the aberrant activation of Ras is associated with tumor-related processes. Several studies have indicated that indole and its derivatives can target regulatory factors and interfere with or even block the aberrant Ras-Related pathway to treat or improve malignant tumors. In this review, we summarize the roles of indole and its derivatives in the isoprenylcysteine carboxyl methyltransferase-participant Ras membrane localization signaling pathway and Ras-GTP/Raf/MAPK signaling pathway through their regulatory mechanisms. Moreover, we briefly discuss the current treatment strategies that target these pathways. Our review will help guide the further study of the application of Ras-Related signaling pathway inhibitors.

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“…For suppressing RAS-dependent signaling, several distinct series of small molecule activators that bind to a hydrophobic pocket in SOS1 in a RAS-SOS1-RAS ternary complex were discovered. Some of these binders activated the SOS1-mediated nucleotide exchange, resulting in reduced RAS signaling through negative feedback on SOS1 [25,26,27]. Most recently, the inhibitor of SOS1 was reported [28].…”

Section: Gef Structures and Mechanisms Of Small Gtpase Activationmentioning

confidence: 99%

Structural Insights into the Regulation Mechanism of Small GTPases by GEFs

Toma-Fukai

Shimizu

2019

Molecules

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Small GTPases are key regulators of cellular events, and their dysfunction causes many types of cancer. They serve as molecular switches by cycling between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound states. GTPases are deactivated by GTPase-activating proteins (GAPs) and are activated by guanine-nucleotide exchange factors (GEFs). The intrinsic GTP hydrolysis activity of small GTPases is generally low and is accelerated by GAPs. GEFs promote GDP dissociation from small GTPases to allow for GTP binding, which results in a conformational change of two highly flexible segments, called switch I and switch II, that enables binding of the gamma phosphate and allows small GTPases to interact with downstream effectors. For several decades, crystal structures of many GEFs and GAPs have been reported and have shown tremendous structural diversity. In this review, we focus on the latest structural studies of GEFs. Detailed pictures of the variety of GEF mechanisms at atomic resolution can provide insights into new approaches for drug discovery.

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Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling

Cited by 32 publications

References 39 publications

Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen

Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen

Regulation of the Ras-Related Signaling Pathway by Small Molecules Containing an Indole Core Scaffold: A Potential Antitumor Therapy

Structural Insights into the Regulation Mechanism of Small GTPases by GEFs

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