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

Raphael Reinbold, Ingvild C. Hvinden, Patrick Rabe, Ryan A. Herold, Alina Finch, James Wood, Melissa Morgan, Maximillian Staudt, Ian J. Clifton, Fraser A. Armstrong, James S. O. McCullagh, Jo Redmond, Chiara Bardella, Martine I. Abboud () and Christopher J. Schofield ()
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Raphael Reinbold: University of Oxford
Ingvild C. Hvinden: University of Oxford
Patrick Rabe: University of Oxford
Ryan A. Herold: University of Oxford
Alina Finch: University of Birmingham
James Wood: University of Birmingham
Melissa Morgan: University of Birmingham
Maximillian Staudt: University of Freiburg
Ian J. Clifton: University of Oxford
Fraser A. Armstrong: University of Oxford
James S. O. McCullagh: University of Oxford
Jo Redmond: GlaxoSmithKline, Gunnels Wood Rd
Chiara Bardella: University of Birmingham
Martine I. Abboud: University of Oxford
Christopher J. Schofield: University of Oxford

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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 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.

Date: 2022
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DOI: 10.1038/s41467-022-32436-4

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