From KRAS G12D to Pan-KRAS Inhibitors─A Journey Enabled by Synthetic Innovation and Structure-Based Drug Design

Xiaoshen Ma; David L. Sloman; Timothy J. Henderson; D. Jonathan Bennett; Gianni Chessari; Philip J. Day; Ruchia Duggal; Emma K. Edelstein; Symon Gathiaka; Andrew J. Hoover; Steven Howard; Shuhei Kawamura; Yu Kobayakawa; Brian M. Lacey; Thomas W. Lyons; My Sam Mansueto; Richard Miller; Shinji Mizuarai; Erik V. Munsell; Marc O’Reilly; Tsuyoshi Oshima; Ryan D. Otte; Anandan Palani; DC Rees; Takeshi Sagara; Aaron C. Sather; Patrick Schöpf; Kazuaki SHIBATA; Yuki Shikata; Nicolas Solban; Sriraman Venkataraman; Dan Su; Uma Swaminathan; Yingchun Ye; Alexander Stoeck; Yongxin Han

doi:10.1021/acs.jmedchem.5c03662

Key Points

The aim is to explore the discovery of inhibitors specific to KRAS mutations, particularly KRASG12D, and to evolve towards pan-KRAS inhibitors.
Described synthetic innovations used in drug development.
Discussed structure-based drug design techniques employed.
Analyzed the development path from KRASG12D inhibitors to pan-KRAS inhibitors.
Identified KRASG12C specific covalent inhibitors like MK-1084.
Outlined progress towards developing KRASG12D specific inhibitors.
Demonstrated the potential of synthetic methods in creating pan-KRAS inhibitors.

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Implication

This article uncovers efforts to develop specific inhibitors for KRAS mutations, indicating a significant advancement in oncology treatments.

Abstract

KRAS, a significant oncology target, has been challenging to develop drugs for until recent discoveries of KRASG12C mutant-specific covalent inhibitors, including MK-1084. This article describes efforts toward the discovery of KRASG12D mutant-specific inhibitors and how synthetic innovations and structure-based drug design were utilized to facilitate the discovery of pan-KRAS inhibitors.

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Ma et al. (2026) studied this question.

synapsesocial.com/papers/69d9e57078050d08c1b75af1 https://doi.org/10.1021/acs.jmedchem.5c03662

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From KRAS G12D to Pan-KRAS Inhibitors─A Journey Enabled by Synthetic Innovation and Structure-Based Drug Design

Key Points

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Implication

Abstract

Discussion

Cite This Study

From KRAS G12D to Pan-KRAS Inhibitors─A Journey Enabled by Synthetic Innovation and Structure-Based Drug Design

Key Points

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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