February 8, 2024Open Access

Supplementary Figures S1 to S11 from Allosteric PI3Kα Inhibition Overcomes On-target Resistance to Orthosteric Inhibitors Mediated by Secondary PIK3CA Mutations

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Allosteric PI3Kα inhibition suppresses tumors harboring secondary pik3ca mutations, overcoming the targeted resistance observed with conventional orthosteric inhibitors.
Free energy perturbation calculations and surface plasmon resonance assays reveal reduced binding of orthosteric inhibitors like alpelisib across diverse double mutants.
Evaluating allosteric candidate rly-2608 demonstrates sustained potency against selected variants, but cell line models require further in vivo validation.

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Implication

Preclinical study demonstrates that allosteric PI3Kα inhibition overcomes orthosteric resistance in breast cancer cells, highlighting a rescue strategy against secondary PIK3CA mutations.

Cite This Study

Varkaris et al. (2024) studied this question.

synapsesocial.com/papers/68e7b92eb6db64358770f10b https://doi.org/10.1158/2159-8290.25191551

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Implication

Preclinical study demonstrates that allosteric PI3Kα inhibition overcomes orthosteric resistance in breast cancer cells, highlighting a rescue strategy against secondary PIK3CA mutations.

Supplementary Figures S1 to S11 from Allosteric PI3Kα Inhibition Overcomes On-target Resistance to Orthosteric Inhibitors Mediated by Secondary PIK3CA Mutations

Key Points

Discussion

Implication

Cite This Study

Supplementary Figures S1 to S11 from Allosteric PI3Kα Inhibition Overcomes On-target Resistance to Orthosteric Inhibitors Mediated by Secondary PIK3CA Mutations

Key Points

Discussion

Implication

Cite This Study

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