KRAS Q61H Mutation Confers Cancer Cells with Acquired Resistance to SHP2 Inhibition

Song, Yihui; Yang, Xinyu; Yu, Bin

doi:10.1055/s-0042-1743411

Cited by 3 publications

(2 citation statements)

References 15 publications

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“…Among them, only the chemical structures of TNO155, HBI‐2376, BBP‐398, and JAB‐3068 have been disclosed (Figure 1). Given the drug resistance of reported SHP2 inhibitors, in‐depth characterization of the underlying pathogenesis mechanism of mutant SHP2 proteins may facilitate the development of inhibitors targeting SHP2 mutations for patients with specific adaptive resistant mutations 17–20 …”

Section: Introductionmentioning

confidence: 99%

“…Given the drug resistance of reported SHP2 inhibitors, indepth characterization of the underlying pathogenesis mechanism of mutant SHP2 proteins may facilitate the development of inhibitors targeting SHP2 mutations for patients with specific adaptive resistant mutations. [17][18][19][20] In this review, we highlight the structural basis underlying the dynamic process of SHP2 under physiological and pathological conditions, binding models of SHP2 inhibitors, and structure-based design of proteolysis-targeting chimeras (PROTAC)-based degraders. We also briefly discuss the combination therapy of SHP2 inhibitors binding to different subpockets or with other anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

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Crystallographic landscape of SHP2 provides molecular insights for SHP2 targeted drug discovery

Song

Yang

Wang

et al. 2022

Medicinal Research Reviews

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The protein tyrosine phosphatase SHP2 encoded by PTPN11 is a promising therapeutic target for cancer therapy. The dynamic change of SHP2 between closed and open conformations under either physiological or pathological conditions provides opportunities to design SHP2 inhibitors for treating SHP2-related diseases. To date, several SHP2 allosteric inhibitors have advanced into clinical trials as mono-or combined therapy of cancers. In this review, we provide an overview on the structural landscape of SHP2 under physiological and pathological conditions and also comprehensively analyze the binding models of SHP2/inhibitor complexes. Structural features of SHP2 under pathological conditions and co-crystal structures of SHP2/inhibitor complexes will definitely facilitate structure-guided design of SHP2 inhibitors. Finally, proteolysis targeting chimeric (PROTAC) based SHP2 degraders have shown therapeutic promise for cancer therapy and are also briefly discussed. We hope this review could provide

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Section: Introductionmentioning

confidence: 99%