Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome

Rao, Suman; Gurbani, Deepak; Du, Guocheng; Everley, Robert A.; Browne, Christopher M.; Chaikuad, A.; Li, Tan; Schröder, Martin; Gondi, Sudershan; Ficarro, Scott B.; Sim, Taebo; Kim, Nam Doo; Berberich, Matthew J.; Knapp, S.; Marto, Jarrod A.; Westover, Kenneth D.; Sorger, Peter K.; Gray, Nathanael S.

doi:10.1016/j.chembiol.2019.02.021

Cited by 48 publications

(51 citation statements)

References 79 publications

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“…In addition, the presence of accessible cysteine residues within the MKK7 ATP binding pocket opens also an opportunity for irreversible targeting strategy 34 , supported by previous observations of covalent binding the natural product 5Z-7-oxzeaenol and promiscuous aminopyrimidine SM1-71 with the kinase domain [35][36][37] . In addition, previous studies have demonstrated that ibrutinib which is an BTK inhibitor can interact covalently with MKK7 in cells 37,38 .…”

Section: Introductionmentioning

confidence: 71%

Catalytic domain plasticity of MKK7 reveals structural mechanisms of allosteric activation and new targeting opportunities

Schröder

Wang

et al. 2020

Preprint

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MKK7 (MEK7) is a key regulator of the JNK stress signaling pathway and targeting MKK7 has been proposed as a chemotherapeutic strategy. Detailed understanding of the MKK7 structure and factors that impact its activity is therefore of critical importance. Here, we present a comprehensive set of MKK7 crystal structures revealing insights into catalytic domain plasticity and the role of the N-terminal regulatory helix, conserved in all MAP2Ks, mediating kinase activation. Crystal structures harboring this regulatory helix revealed typical structural features of active kinase, providing exclusively a first model of the MAP2K active state. A small molecule screening campaign yielded multiple scaffolds, including type-II irreversible inhibitors a binding mode that has not been reported previously. We also observed an unprecedented allosteric pocket located in the N-terminal lobe for the approved drug ibrutinib. Collectively, our structural and functional data expand and provide alternative targeting strategies for this important MAP2K kinase.

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Section: Introductionmentioning

confidence: 71%

Catalytic domain plasticity of MKK7 reveals structural mechanisms of allosteric activation and new targeting opportunities

Schröder

Wang

et al. 2020

Preprint

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“…By utilizing a multitargeted kinase inhibitor, SM1-71, that serves as an effective tool compound we were able to elucidate molecular mechanisms driving specific cancer cell types. In our previous study, we used SM1-71 to interrogate the human kinome to identify cysteines that can be targeted because of the covalent nature of the compound (45). In the present study, we extended the use of this compound to the investigation of signaling pathways that drive cellular proliferation in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…1a). We previously used chemical proteomic approaches to elucidate ϳ54 kinase targets of SM1-71 (45) (Table S1) and identified 24 kinases as exhibiting an IC 50 value Ͻ10 M ( Table 1). Thirteen of these kinases have well-annotated functions in promoting cell growth and proliferation, including YES1, SRC, MAP2K2 (MEK2), AURKA, MAP2K1 (MEK1), MAP3K1, MAPK1 (ERK2), MAPK3 (ERK1), WEE1, IGF1R, INSR, DDR1, and MET.…”

Section: Investigating the Cytotoxic Effect Of Sm1-71 Across Multiplementioning

confidence: 99%

“…We were especially interested in elucidating druggable targets in KRAS mutant cells because RAS mutations are found across different tumors and lack effective targeted therapy (30,31). We carried out all our analyses in H23-KRAS G12C NSCLC cells, which we recently employed to generate a global map of kinases to which SM1-71 binds (45). To identify kinase targets of SM1-71 responsible for mediating cytotoxic effects in H23-KRAS G12C cells, we measured the phosphorylation status of kinases involved in MAPK and PI3K signaling pathways, two effectors downstream of KRAS, using Western blotting ( Fig.…”

Section: Editors' Pick: Deciphering Cancer Signaling Vulnerabilitiesmentioning

confidence: 99%

“…We conclude that SM1-71 is active on at least three RTKs known to lie upstream of the PI3K signaling pathway. Furthermore, we identified each of these three RTKs, IGF1R, INSR, and MET, as direct targets of SM1-71 from our previous study (Table S1) (45).…”

Section: Editors' Pick: Deciphering Cancer Signaling Vulnerabilitiesmentioning

confidence: 99%

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A multitargeted probe-based strategy to identify signaling vulnerabilities in cancers

Rao

Hafner

et al. 2019

Journal of Biological Chemistry

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Edited by Eric R. FearonMost cancer cells are dependent on a network of deregulated signaling pathways for survival and are insensitive, or rapidly evolve resistance, to selective inhibitors aimed at a single target. For these reasons, drugs that target more than one protein (polypharmacology) can be clinically advantageous. The discovery of useful polypharmacology remains serendipitous and is challenging to characterize and validate. In this study, we developed a non-genetic strategy for the identification of pathways that drive cancer cell proliferation and represent exploitable signaling vulnerabilities. Our approach is based on using a multitargeted kinase inhibitor, SM1-71, as a tool compound to identify combinations of targets whose simultaneous inhibition elicits a potent cytotoxic effect. As a proof of concept, we applied this approach to a KRAS-dependent non-small cell lung cancer (NSCLC) cell line, H23-KRAS G12C . Using a combination of phenotypic screens, signaling analyses, and kinase inhibitors, we found that dual inhibition of MEK1/2 and insulin-like growth factor 1 receptor (IGF1R)/insulin receptor (INSR) is critical for blocking proliferation in cells. Our work supports the value of multitargeted tool compounds with well-validated polypharmacology and target space as tools to discover kinase dependences in cancer. We propose that the strategy described here is complementary to existing genetics-based approaches, generalizable to other systems, and enabling for future mechanistic and translational studies of polypharmacology in the context of signaling vulnerabilities in cancers.

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YES1 as a potential target to overcome drug resistance in EGFR-deregulated non-small cell lung cancer

Kook,

Lee,

Kim

2024

Arch Toxicol

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Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome

Cited by 48 publications

References 79 publications

Catalytic domain plasticity of MKK7 reveals structural mechanisms of allosteric activation and new targeting opportunities

Catalytic domain plasticity of MKK7 reveals structural mechanisms of allosteric activation and new targeting opportunities

A multitargeted probe-based strategy to identify signaling vulnerabilities in cancers

YES1 as a potential target to overcome drug resistance in EGFR-deregulated non-small cell lung cancer

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