Discovery and Optimization of Quinolinone Derivatives as Potent, Selective, and Orally Bioavailable Mutant Isocitrate...

Area of Science:

• Medicinal Chemistry
• Oncology
• Biochemistry

Background:

• Mutations in isocitrate dehydrogenase 1 (IDH1), particularly at the R132 residue, are common in various human cancers.
• Targeting mutant IDH1 (mIDH1) with small molecule inhibitors is a validated therapeutic strategy for hematologic and solid tumors.

Purpose of the Study:

• To discover and optimize potent, orally bioavailable quinolinone-based inhibitors of mIDH1.
• To achieve selectivity for mIDH1 over wild-type IDH1.

Main Methods:

• Structure-based drug design utilizing X-ray crystallography.
• Lead optimization focusing on in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties.
• Preclinical evaluation of a lead compound.

Main Results:

• Discovery of a series of quinolinones as mIDH1 inhibitors.
• Identification of an allosteric binding site for an early lead compound (24) via X-ray crystallography.
• Optimization of ADME properties led to a preclinical candidate (63) with favorable characteristics.

Conclusions:

• Quinolinone derivatives represent a promising class of orally bioavailable mIDH1 inhibitors.
• Preclinical candidate 63 demonstrates potential for further development in human clinical trials.
• The identified allosteric binding mode provides insights for future inhibitor design.