Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor.

Abstract

Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.

• Authors: Justin A Caravella, Jian Lin, R Bruce Diebold, Ann-Marie Campbell, Anna Ericsson, Gary Gustafson, Zhongguo Wang, Jennifer Castro, Andrea Clarke, Deepali Gotur, Helen R Josephine, Marie Katz, Mark Kershaw, Lili Yao, Angela V Toms, Kenneth J Barr, Christopher J Dinsmore, Duncan Walker, Susan Ashwell, Wei Lu
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 63 Issue 4 Pg. 1612-1623 (02 27 2020) ISSN: 1520-4804 [Electronic] United States
• PMID: 31971798 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Pyridines
• Quinolines
• Quinolones
• olutasidenib
• Isocitrate Dehydrogenase
• IDH1 protein, human

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, metabolism, therapeutic use)
• Cell Line, Tumor
• Drug Design
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (chemical synthesis, metabolism, therapeutic use)
• Female
• Humans
• Isocitrate Dehydrogenase (antagonists & inhibitors, metabolism)
• Mice, Inbred BALB C
• Molecular Structure
• Neoplasms (drug therapy)
• Protein Binding
• Pyridines (chemical synthesis, metabolism, therapeutic use)
• Quinolines (chemical synthesis, metabolism, therapeutic use)
• Quinolones (chemical synthesis, metabolism, therapeutic use)
• Structure-Activity Relationship
• Xenograft Model Antitumor Assays