Abstract 6417: LY3410738, a novel inhibitor of mutant IDH1 is more effective than Ivosidenib and potentiates antileukemic activity of standard chemotherapy in preclinical models of acute myeloid leukemia (AML)

Abstract

Acute myeloid leukemia is associated with the abnormal proliferation of myeloid progenitor cells unable to differentiate. Somatic gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 occur in 10% of newly diagnosed AML patients. IDH1 mutations cause intracellular accumulation of the oncometabolite, 2-hydroxyglutarate (2-HG), which results in a hyper-methylation phenotype and a block in differentiation. Inhibitors of IDH1 mutant enzyme reduce levels of 2-HG, which relieves the differentiation block allowing AML cells to achieve terminal maturation. Recently, Ivosidenib, an IDH1 inhibitor, has been approved for use in AML patients. However, based on clinical findings, a fraction of the IDH1 mutant AML patients treated with Ivosidenib are primary refractory or relapse while on therapy. This raises the need for development of more potent inhibitors targeting IDH1. Lilly Research Laboratories have developed a potent covalent inhibitor of mutant IDH1, LY3410738 that modifies a single cysteine (Cys269) in an allosteric binding pocket and rapidly inactivates the enzyme, selectively inhibiting 2-HG production without affecting alpha-ketoglutarate (a-KG) levels. Here, we have assessed the activity of LY3410738 in IDH1 mutated patient-derived AML models and AML cell lines engineered to express wild-type IDH1 or mutant IDH1R132H. In vitro, LY3410738 displayed greater potency for inhibition of 2-HG production and differentiation of the IDH1 mutant cells compared to AG-120. Similarly, in vivo, we observed sustained 2-HG inhibition leading to a more robust and durable efficacy for LY3410738 with respect to AG-120. We next evaluated the combination activity of LY3410738 with Cytarabine and Azacitidine or the FLT3 inhibitor Midostaurin, the latter in FLT3-mutated AML. Combining LY3410738 with the chemotherapeutics resulted in increased efficacy, exhibiting a potent anti-leukemic effect, reduction of 2-HG level, and enhanced differentiation of the leukemic blasts in the mice. In addition, since IDH1 mutant AML cells have been shown to strongly depend on the anti-apoptotic Bcl-2 for the survival, we also combined LY3410738 with FDA approved Bcl-2 inhibitor, venetoclax. In vitro, isogenic cells with IDH1R132H mutation were more sensitive to the combination than wild-type IDH1-expressing cells. Importantly, the combination of LY3410738 with Venetoclax was also efficacious in an AML xenograft model derived from a patient refractory to AG-120. In conclusion, LY3410738 exhibits enhanced efficacy in IDH1 mutant AML PDX models in combination with Cytarabine, Azacitidine, Midostaurin and Venetoclax and demonstrates improved potency and durability compared to Ivosidenib. Citation Format: Vivian Salama, Nathan Brooks, Anna Skwarska, Lisa Kays, Paul Milligan, Katherine Newell, Kenneth Roth, Sandaruwan Geeganage, Raymond Gilmour, Steven M. Chan, Jean-Emmanuel Sarry, Mary Sabatier, Courtney DiNardo, Marina Konopleva. LY3410738, a novel inhibitor of mutant IDH1 is more effective than Ivosidenib and potentiates antileukemic activity of standard chemotherapy in preclinical models of acute myeloid leukemia (AML) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6417.

Secondary IDH1 resistance mutations and oncogenic IDH2 mutations cause acquired resistance to ivosidenib in cholangiocarcinoma

“…3d, e ). Finally, we found that the structurally unrelated mutant IDH1 inhibitor LY3410738 22 (Fig. 4 ) potently suppressed both (R) -2HG production and cytokine independence in IDH1 R132H/D279N-expressing TF-1 cells (Fig.…”

“…The chemical structure of ivosidenib was retrieved from PubChem (National Center for Biotechnology Information, PubChem Compound Summary for CID71657455, https://pubchem.ncbi.nlm.nih.gov/compound/Ivosidenib , accessed 6 October 2021). The chemical structure of LY3410738 is in the public domain 22 . Protonation states at pH 7.4 and tridimensional geometries were calculated by JChem (version 21.18, www.chemaxon.com ).…”

Acute myeloid leukemia in elderly patients: New targets, new therapies

“…While the co‐crystal structure has illustrated the binding pockets of IDH inhibitors, 146 the development of a new IDH inhibitor that binds to a binding pocket distant from secondary site mutations would be a feasible pharmaceutical strategy to overcome acquired resistance for treating IDH‐mutated AML patients. Indeed, LY3410738, a covalent inhibitor that targets IDH1 by binding to Cys269 in the allosteric binding pocket that is distinct from where ivosidenib binds, has demonstrated improved potency and durability compared to ivosidenib both in vitro and in vivo, suggesting its promising potential for clinical use for targeting secondary site mutations on IDH1 and thus overcoming resistance 147,148 …”

“…Indeed, LY3410738, a covalent inhibitor that targets IDH1 by binding to Cys269 in the allosteric binding pocket that is distinct from where ivosidenib binds, has demonstrated improved potency and durability compared to ivosidenib both in vitro and in vivo, suggesting its promising potential for clinical use for targeting secondary site mutations on IDH1 and thus overcoming resistance. 147,148 Acquired modifications that often lead to either reactivation or persistent activation of signaling pathways essential for cell survival following drug treatment have also been commonly observed in drug-resistant AML cells. For the case of patients with FLT3-mutated AML, this type of resistance has been commonly observed in those treated with type 1 inhibitors that target both FLT3-ITD and FLT3-TKD mutations.…”

Single-Cell Metabolomics in Hematopoiesis and Hematological Malignancies

“…IDH mutations are prone to occur in AML ( 50 , 51 ), and the FDA-approved drugs ivosidenib and enasidenib have been identified as small molecules, targeting IDH1 and IDH2 in AML, respectively. Furthermore, vorasidenib (AG-881) and LY3410738 are under investigation in phase I trials for the treatment of AML patients with IDH1 and/or IDH2 mutation ( 52 , 53 ).…”