Synthesis, Biological Evaluation, and Binding Mode of a New Class of Oncogenic K‐Ras4b Inhibitors

Jeuken, Stephan; Shkura, Oleksandr; Röger, Marc; Brickau, Victoria; Choidas, Axel; Degenhart, Carsten; Gülden, Daniel; Klebl, Bert; Koch, Uwe; Stoll, Raphael; Scherkenbeck, Jürgen

doi:10.1002/cmdc.202200392

Cited by 2 publications

(1 citation statement)

References 60 publications

(121 reference statements)

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“…The success of covalent inhibition of KRAS(G12C) to its switch-II pocket (SII-P) (reviewed in , ) is exemplified by the first clinically approved KRAS-targeting drugs sotorasib and adagrasib . , This success has cultivated the currently ongoing efforts to target the SII-P of other KRAS mutants beyond G12C, including G12D, G12S, and G12R . However, a number of other approaches toward direct KRAS targeting with small molecules, such as targeting SI/SII (switch-I/switch-II) site, have mainly resulted in lower-affinity compounds. − Therefore, SII-P appears to offer the most promising approach to tackle this oncoprotein with small-molecule inhibitors that have been reported to date.…”

Section: Introductionmentioning

confidence: 99%

In Silico Evaluation of the Thr58-Associated Conserved Water with KRAS Switch-II Pocket Binders

Leini

2023

J. Chem. Inf. Model.

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The KRAS switch-II pocket (SII-P) has proven to be one of the most successful tools for targeting KRAS with small molecules to date. This has been demonstrated with several KRAS(G12C)-targeting covalent inhibitors, already resulting in two FDA-approved drugs. Several earlier-stage compounds have also been reported to engage KRAS SII-P with other position 12 mutants, including G12D, G12S, and G12R. A highly conserved water molecule exists in the KRAS SII-P, linking Thr58 of switch-II and Gly10 of β1 sheet. This conserved water is also present in the cocrystal structures of most of the disclosed small-molecule inhibitors but is only displaced by a handful of SII-P binders. Here, we evaluated the conserved water molecule energetics by the WaterMap for the SII-P binders with publicly disclosed structures and studied the water behavior in the presence of selected inhibitors by microsecond timescale molecular dynamics (MD) simulations using two water models (total simulation time of 120 μs). Our data revealed the high-energy nature of this hydration site when coexisting with an SII-P binder and that there is a preference for a single isolated hydration site in this location within the most advanced compounds. Furthermore, water displacement was only achieved with a few disclosed compounds and was suboptimal, as for instance a cyanomethyl group as a water displacer appears to introduce repulsion with the native conformation of Thr58. These results suggested that this conserved water should be considered more central when designing new inhibitors, especially in the design of noncovalent inhibitors targeting the SII-P.

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Section: Introductionmentioning

confidence: 99%

In Silico Evaluation of the Thr58-Associated Conserved Water with KRAS Switch-II Pocket Binders

Leini

2023

J. Chem. Inf. Model.

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Synthesis, Biological Evaluation, and Binding Mode of a New Class of Oncogenic K‐Ras4b Inhibitors

et al. 2022

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Ras proteins are implicated in some of the most common life‐threatening cancers. Despite intense research during the past three decades, progress towards small‐molecule inhibitors of mutant Ras proteins still has been limited. Only recently has significant progress been made, in particular with ligands for binding sites located in the switch II and between the switch I and switch II region of K‐Ras4B. However, the structural diversity of inhibitors identified for those sites to date is narrow. Herein, we show that hydrazones and oxime ethers of specific bis(het)aryl ketones represent structurally variable chemotypes for new GDP/GTP‐exchange inhibitors with significant cellular activity.

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Synthesis, Biological Evaluation, and Binding Mode of a New Class of Oncogenic K‐Ras4b Inhibitors

Cited by 2 publications

References 60 publications

In Silico Evaluation of the Thr58-Associated Conserved Water with KRAS Switch-II Pocket Binders

In Silico Evaluation of the Thr58-Associated Conserved Water with KRAS Switch-II Pocket Binders

Synthesis, Biological Evaluation, and Binding Mode of a New Class of Oncogenic K‐Ras4b Inhibitors

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