Inhibitor potency varies widely among tumor-relevant human isocitrate dehydrogenase 1 mutants.

Autor: Avellaneda Matteo D; Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, U.S.A., Wells GA; Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, U.S.A., Luna LA; Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, U.S.A., Grunseth AJ; Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, U.S.A., Zagnitko O; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, U.S.A., Scott DA; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, U.S.A., Hoang A; Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, U.S.A., Luthra A; Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, U.S.A., Swairjo MA; Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, U.S.A., Schiffer JM; Schrödinger, La Jolla, CA, U.S.A. jamie.schiffer@schrodinger.com csohl@sdsu.edu., Sohl CD; Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, U.S.A. jamie.schiffer@schrodinger.com csohl@sdsu.edu.
Jazyk: angličtina
Zdroj: The Biochemical journal [Biochem J] 2018 Oct 22; Vol. 475 (20), pp. 3221-3238. Date of Electronic Publication: 2018 Oct 22.
DOI: 10.1042/BCJ20180424
Abstrakt: Mutations in isocitrate dehydrogenase 1 (IDH1) drive most low-grade gliomas and secondary glioblastomas and many chondrosarcomas and acute myeloid leukemia cases. Most tumor-relevant IDH1 mutations are deficient in the normal oxidization of isocitrate to α-ketoglutarate (αKG), but gain the neomorphic activity of reducing αKG to D-2-hydroxyglutarate (D2HG), which drives tumorigenesis. We found previously that IDH1 mutants exhibit one of two reactivities: deficient αKG and moderate D2HG production (including commonly observed R132H and R132C) or moderate αKG and high D2HG production (R132Q). Here, we identify a third type of reactivity, deficient αKG and high D2HG production (R132L). We show that R132Q IDH1 has unique structural features and distinct reactivities towards mutant IDH1 inhibitors. Biochemical and cell-based assays demonstrate that while most tumor-relevant mutations were effectively inhibited by mutant IDH1 inhibitors, R132Q IDH1 had up to a 16 300-fold increase in IC 50 versus R132H IDH1. Only compounds that inhibited wild-type (WT) IDH1 were effective against R132Q. This suggests that patients with a R132Q mutation may have a poor response to mutant IDH1 therapies. Molecular dynamics simulations revealed that near the NADP + /NADPH-binding site in R132Q IDH1, a pair of α-helices switches between conformations that are more wild-type-like or more mutant-like, highlighting mechanisms for preserved WT activity. Dihedral angle changes in the dimer interface and buried surface area charges highlight possible mechanisms for loss of inhibitor affinity against R132Q. This work provides a platform for predicting a patient's therapeutic response and identifies a potential resistance mutation that may arise upon treatment with mutant IDH inhibitors.
(© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
Databáze: MEDLINE
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