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Discovery of HMPL-306 (Ranosidenib), a New Potent and Selective Dual Inhibitor of Mutant IDH1 and 2 in Clinical

Kun Xiao1, Zheng Zhang1, Yao Wu1

  • 1HUTCHMED Limited, Building 4, 720 Cai Lun Road, Zhangjiang Hi-Tech Park, 201203 Shanghai, China.

ACS Medicinal Chemistry Letters
|March 19, 2025
PubMed

Insights

Novel mutant isocitrate dehydrogenase (IDH) inhibitor HMPL-306 (ranosidenib) effectively reduces (R)-2-hydroxyglutarate (2-HG) in preclinical models and shows promising safety and efficacy in patients with IDH-mutated myeloid malignancies.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Pharmacology

Background:

  • Mutations in isocitrate dehydrogenase (IDH) 1 or 2 are drivers in various cancers.
  • Accumulation of (R)-2-hydroxyglutarate (2-HG) by mutant IDH inhibits cell differentiation and promotes malignant transformation.

Purpose of the Study:

  • To discover and optimize a novel dual inhibitor of mutant IDH1 and IDH2.
  • To evaluate the preclinical and clinical profile of HMPL-306 (ranosidenib).

Main Methods:

  • Structure-activity relationship (SAR) studies and pharmacokinetic optimization were employed.
  • Preclinical studies assessed HMPL-306's potency, selectivity, pharmacokinetics, safety, and in vivo 2-HG reduction in xenograft models.
  • Clinical studies evaluated safety and efficacy in patients with relapsed/refractory myeloid malignancies.

Main Results:

  • HMPL-306 was identified as a potent and selective dual inhibitor of mutant IDH1 and IDH2.
  • Preclinical studies demonstrated favorable pharmacokinetics, safety, robust 2-HG reduction, and high brain penetration.
  • Clinical trials indicated good safety and encouraging efficacy in patients with IDH-mutated myeloid malignancies.

Conclusions:

  • HMPL-306 (ranosidenib) is a promising therapeutic candidate for IDH-mutated cancers.
  • The drug effectively targets mutant IDH, reduces 2-HG levels, and shows clinical benefit in myeloid malignancies.

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