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Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors

Abstract:

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 ...

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Publication status:
Published
Peer review status:
Peer reviewed

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Publisher copy:
10.1038/s41467-022-32436-4

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Role:
Author
ORCID:
0000-0002-7181-6790
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Role:
Author
ORCID:
0000-0002-3205-9969
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Author
ORCID:
0000-0002-3448-9559
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Role:
Author
ORCID:
0000-0001-7935-6269
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Role:
Author
ORCID:
0000-0002-5021-2111
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Name:
Biotechnology and Biological Sciences Research Council
Grant:
BB/J001694/2
BB/L000121/1
BB/R013829/1
Publisher:
Springer Nature
Journal:
Nature Communications More from this journal
Volume:
13
Article number:
4785
Publication date:
2022-08-15
Acceptance date:
2022-07-25
DOI:
EISSN:
2041-1723
Pmid:
35970853
Language:
English
Keywords:
Pubs id:
1274389
Local pid:
pubs:1274389
Deposit date:
2022-11-22

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