Oncology Pipeline

The enzyme isocitrate dehydrogenase (IDH1) is mutated in a variety of cancers, including acute myeloid leukemia (AML), cholangiocarcinoma, chondrosarcoma, and glioma.^2-5 These mutations are typically somatic gain-of-function mutations located in arginine 132 (R132) that grant IDH1 the ability to produce 2-hydroxyglutarate (2-HG).⁶ 2-HG is an oncometabolite that promotes tumor development by inhibiting enzymes that maintain normal DNA and histone methylation, leading to hypermethylation associated with transcriptional dysregulation.^6,7 As a result, IDH1-mutated cells become blocked in a progenitor-like state and contribute to tumor development both directly through cellular self-renewal and indirectly through cooperation with other oncogenic drivers.⁷

LY3410738 is a potent, selective, and covalent inhibitor of mutant IDH1 that has been shown in vitro and in vivo to rapidly inactivate mutant IDH1 and inhibit 2-HG production without impacting wild-type IDH1.⁸