2. Academic Validation
  3. Identification of novel allosteric inhibitors of mutant isocitrate dehydrogenase 1 by cross docking-based virtual screening

Identification of novel allosteric inhibitors of mutant isocitrate dehydrogenase 1 by cross docking-based virtual screening

  • Bioorg Med Chem Lett. 2018 Feb 1;28(3):388-393. doi: 10.1016/j.bmcl.2017.12.030.
Fangxia Zou 1,  Stefan Pusch 2,  Jie Hua 3,  Tianfang Ma 1,  Lijun Yang 4,  Qihua Zhu 5,  Yungen Xu 5,  Yueqing Gu 4,  Andreas von Deimling 6,  Xiaoming Zha 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Engineering & Department of Biochemical Engineering, School of Engineering, China Pharmaceutical University, 539 Longmian Avenue, Nanjing 211198, PR China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 2 German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), INF 280, Heidelberg D-69120, Germany; Department of Neuropathology, Institute of Pathology, INF 224, Ruprecht-Karls-University Heidelberg, Heidelberg D-69120, Germany.
  • 3 Department of Gastroenterology, The First Affliated Hospital with Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, PR China.
  • 4 Department of Pharmaceutical Engineering & Department of Biochemical Engineering, School of Engineering, China Pharmaceutical University, 539 Longmian Avenue, Nanjing 211198, PR China.
  • 5 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 6 German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), INF 280, Heidelberg D-69120, Germany; Department of Neuropathology, Institute of Pathology, INF 224, Ruprecht-Karls-University Heidelberg, Heidelberg D-69120, Germany. Electronic address: [email protected].
  • 7 Department of Pharmaceutical Engineering & Department of Biochemical Engineering, School of Engineering, China Pharmaceutical University, 539 Longmian Avenue, Nanjing 211198, PR China. Electronic address: [email protected].
PMID: 29290542 DOI: 10.1016/j.bmcl.2017.12.030
Abstract

IDH1 mutation (mIDH1) occurs in 20-30% of gliomas and is a promising target for the Cancer therapy. In this article, a cross docking-based virtual screening was employed to identify seven small molecules for the allosteric site of mIDH1. Compounds ZX01, ZX05 and ZX06 exhibited the potent inhibitory activity and the high selectivity against WT-IDH1, providing a good starting point for the further development of highly selective mIDH1 inhibitors. Importantly, the parallel artificial membrane permeation assay of the blood-brain barrier (PAMPA-BBB) identified ZX06 with a good ability to penetrate BBB. These findings indicate that ZX06 deserves further optimization as a lead compound for the treatment of patients with IDH1 mutated brain cancers.

Keywords

Allosteric; BBB; Docking; Gliomas; Inhibitors; Mutant IDH1.

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