The return of RET GateKeeper mutations? an in-silico exploratory analysis of potential resistance mechanisms to novel RET macrocyclic inhibitor TPX-0046.
Drug resistance
Molecular tumor board
Precision oncology
RET inhibitor
Tyrosine kinase inhibitor
Journal
Investigational new drugs
ISSN: 1573-0646
Titre abrégé: Invest New Drugs
Pays: United States
ID NLM: 8309330
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
24
01
2022
accepted:
16
05
2022
pubmed:
26
5
2022
medline:
25
8
2022
entrez:
25
5
2022
Statut:
ppublish
Résumé
TPX-0046 is designed to overcome resistance to FDA approved RET inhibitors Selpercatinib and Pralsetinib. Early prediction of resistance mechanisms to investigational drugs may facilitate subsequent drug and trial designs. This study aims to predict potential mutations inducing resistance to TPX-0046. We conducted an in-silico analysis of TPX-0046 macrocyclic structure and predicted the binding mode on RET. We used as reference literary examples of resistance mechanisms to other macrocyclic inhibitors (Lorlatinib on ALK/ROS1) to construct RET secondary resistance mutations. We conducted docking simulations to evaluate impact of mutations on TPX-0046 binding. TPX-0046 binding mode on RET appears to not be influenced by Solventfront G810X mutation presence. Bulky Gatekeeper V804X mutations affect predicted TPX-0046 binding mode. Mutations in Beta 7 strand region L881F and xDFG S891L impair TPX-0046 docking. Our findings suggest that development of second generation RET inhibitors focused mainly on Solventfront G810X mutations granting resistance to selective RET inhibitors Selpercatinib and Pralsetinib. If these findings are confirmed by identification of Gatekeeper V804X mutations in patients progressing to TPX-0046, explanation of acquired resistance and loss of benefit will be easier These findings might accelerate development of third generation RET inhibitors, as well as clinical trial design in precision oncology settings.
Identifiants
pubmed: 35612671
doi: 10.1007/s10637-022-01259-x
pii: 10.1007/s10637-022-01259-x
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Proto-Oncogene Proteins
0
Anaplastic Lymphoma Kinase
EC 2.7.10.1
Protein-Tyrosine Kinases
EC 2.7.10.1
Proto-Oncogene Proteins c-ret
EC 2.7.10.1
RET protein, human
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1133-1136Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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