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Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations

NTRK chromosomal rearrangements yield oncogenic TRK fusion proteins that are sensitive to TRK inhibitors (larotrectinib and entrectinib) but often mutate, limiting the durability of response for NTRK(+) patients. Next-generation inhibitors with compact macrocyclic structures (repotrectinib and selit...

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Autores principales: Murray, Brion W., Rogers, Evan, Zhai, Dayong, Deng, Wei, Chen, Xi, Sprengeler, Paul A., Zhang, Xin, Graber, Armin, Reich, Siegfried H., Stopatschinskaja, Shanna, Solomon, Benjamin, Besse, Benjamin, Drilon, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9762329/
https://www.ncbi.nlm.nih.gov/pubmed/34625502
http://dx.doi.org/10.1158/1535-7163.MCT-21-0632
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author Murray, Brion W.
Rogers, Evan
Zhai, Dayong
Deng, Wei
Chen, Xi
Sprengeler, Paul A.
Zhang, Xin
Graber, Armin
Reich, Siegfried H.
Stopatschinskaja, Shanna
Solomon, Benjamin
Besse, Benjamin
Drilon, Alexander
author_facet Murray, Brion W.
Rogers, Evan
Zhai, Dayong
Deng, Wei
Chen, Xi
Sprengeler, Paul A.
Zhang, Xin
Graber, Armin
Reich, Siegfried H.
Stopatschinskaja, Shanna
Solomon, Benjamin
Besse, Benjamin
Drilon, Alexander
author_sort Murray, Brion W.
collection PubMed
description NTRK chromosomal rearrangements yield oncogenic TRK fusion proteins that are sensitive to TRK inhibitors (larotrectinib and entrectinib) but often mutate, limiting the durability of response for NTRK(+) patients. Next-generation inhibitors with compact macrocyclic structures (repotrectinib and selitrectinib) were designed to avoid resistance mutations. Head-to-head potency comparisons of TRK inhibitors and molecular characterization of binding interactions are incomplete, obscuring a detailed understanding of how molecular characteristics translate to potency. Larotrectinib, entrectinib, selitrectinib, and repotrectinib were characterized using cellular models of wild-type TRKA/B/C fusions and resistance mutant variants with a subset evaluated in xenograft tumor models. Crystal structures were determined for repotrectinib bound to TRKA (wild-type, solvent-front mutant). TKI-naïve and pretreated case studies are presented. Repotrectinib was the most potent inhibitor of wild-type TRKA/B/C fusions and was more potent than selitrectinib against all tested resistance mutations, underscoring the importance of distinct features of the macrocycle structures. Cocrystal structures of repotrectinib with wild-type TRKA and the TRKA(G595R) SFM variant elucidated how differences in macrocyclic inhibitor structure, binding orientation, and conformational flexibility affect potency and mutant selectivity. The SFM crystal structure revealed an unexpected intramolecular arginine sidechain interaction. Repotrectinib caused tumor regression in LMNA–NTRK1 xenograft models harboring GKM, SFM, xDFG, and GKM + SFM compound mutations. Durable responses were observed in TKI-naïve and -pretreated patients with NTRK(+) cancers treated with repotrectinib (NCT03093116). This comprehensive analysis of first- and second-generation TRK inhibitors informs the clinical utility, structural determinants of inhibitor potency, and design of new generations of macrocyclic inhibitors.
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spelling pubmed-97623292023-01-05 Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations Murray, Brion W. Rogers, Evan Zhai, Dayong Deng, Wei Chen, Xi Sprengeler, Paul A. Zhang, Xin Graber, Armin Reich, Siegfried H. Stopatschinskaja, Shanna Solomon, Benjamin Besse, Benjamin Drilon, Alexander Mol Cancer Ther Small Molecule Therapeutics NTRK chromosomal rearrangements yield oncogenic TRK fusion proteins that are sensitive to TRK inhibitors (larotrectinib and entrectinib) but often mutate, limiting the durability of response for NTRK(+) patients. Next-generation inhibitors with compact macrocyclic structures (repotrectinib and selitrectinib) were designed to avoid resistance mutations. Head-to-head potency comparisons of TRK inhibitors and molecular characterization of binding interactions are incomplete, obscuring a detailed understanding of how molecular characteristics translate to potency. Larotrectinib, entrectinib, selitrectinib, and repotrectinib were characterized using cellular models of wild-type TRKA/B/C fusions and resistance mutant variants with a subset evaluated in xenograft tumor models. Crystal structures were determined for repotrectinib bound to TRKA (wild-type, solvent-front mutant). TKI-naïve and pretreated case studies are presented. Repotrectinib was the most potent inhibitor of wild-type TRKA/B/C fusions and was more potent than selitrectinib against all tested resistance mutations, underscoring the importance of distinct features of the macrocycle structures. Cocrystal structures of repotrectinib with wild-type TRKA and the TRKA(G595R) SFM variant elucidated how differences in macrocyclic inhibitor structure, binding orientation, and conformational flexibility affect potency and mutant selectivity. The SFM crystal structure revealed an unexpected intramolecular arginine sidechain interaction. Repotrectinib caused tumor regression in LMNA–NTRK1 xenograft models harboring GKM, SFM, xDFG, and GKM + SFM compound mutations. Durable responses were observed in TKI-naïve and -pretreated patients with NTRK(+) cancers treated with repotrectinib (NCT03093116). This comprehensive analysis of first- and second-generation TRK inhibitors informs the clinical utility, structural determinants of inhibitor potency, and design of new generations of macrocyclic inhibitors. American Association for Cancer Research 2021-12-01 2021-10-08 /pmc/articles/PMC9762329/ /pubmed/34625502 http://dx.doi.org/10.1158/1535-7163.MCT-21-0632 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Small Molecule Therapeutics
Murray, Brion W.
Rogers, Evan
Zhai, Dayong
Deng, Wei
Chen, Xi
Sprengeler, Paul A.
Zhang, Xin
Graber, Armin
Reich, Siegfried H.
Stopatschinskaja, Shanna
Solomon, Benjamin
Besse, Benjamin
Drilon, Alexander
Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations
title Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations
title_full Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations
title_fullStr Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations
title_full_unstemmed Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations
title_short Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations
title_sort molecular characteristics of repotrectinib that enable potent inhibition of trk fusion proteins and resistant mutations
topic Small Molecule Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9762329/
https://www.ncbi.nlm.nih.gov/pubmed/34625502
http://dx.doi.org/10.1158/1535-7163.MCT-21-0632
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