Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 08 2022
15 08 2022
Historique:
received:
11
04
2022
accepted:
25
07
2022
entrez:
15
8
2022
pubmed:
16
8
2022
medline:
18
8
2022
Statut:
epublish
Résumé
Ivosidenib, an inhibitor of isocitrate dehydrogenase 1 (IDH1) R132C and R132H variants, is approved for the treatment of acute myeloid leukaemia (AML). Resistance to ivosidenib due to a second site mutation of IDH1 R132C, leading to IDH1 R132C/S280F, has emerged. We describe biochemical, crystallographic, and cellular studies on the IDH1 R132C/S280F and R132H/S280F variants that inform on the mechanism of second-site resistance, which involves both modulation of inhibitor binding at the IDH1 dimer-interface and alteration of kinetic properties, which enable more efficient 2-HG production relative to IDH1 R132C and IDH1 R132H. Importantly, the biochemical and cellular results demonstrate that it should be possible to overcome S280F mediated resistance in AML patients by using alternative inhibitors, including some presently in phase 2 clinical trials.
Identifiants
pubmed: 35970853
doi: 10.1038/s41467-022-32436-4
pii: 10.1038/s41467-022-32436-4
pmc: PMC9378673
doi:
Substances chimiques
Pyridines
0
Isocitrate Dehydrogenase
EC 1.1.1.41
IDH1 protein, human
EC 1.1.1.42.
ivosidenib
Q2PCN8MAM6
Glycine
TE7660XO1C
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4785Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/R506655/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/L000121/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/J001694/2
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/R013829/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 091857/7/10/7
Pays : United Kingdom
Organisme : Medical Research Council
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C8717/A18245
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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