2. Academic Validation
  3. Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma

Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma

  • J Med Chem. 2020 Sep 10;63(17):10061-10085. doi: 10.1021/acs.jmedchem.0c01199.
David Smil 1,  Jong Fu Wong 2,  Eleanor P Williams 2,  Roslin J Adamson 2,  Alison Howarth 2,  David A McLeod 1,  Ahmed Mamai 1,  Soyoung Kim 1,  Brian J Wilson 1,  Taira Kiyota 1,  Ahmed Aman 1 3,  Julie Owen 1,  Gennady Poda 1 3,  Kurumi Y Horiuchi 4,  Ekaterina Kuznetsova 4,  Haiching Ma 4,  J Nicole Hamblin 5,  Sue Cramp 6,  Owen G Roberts 7,  Aled M Edwards 7 8,  David Uehling 1,  Rima Al-Awar 1 9,  Alex N Bullock 2,  Jeff A O'Meara 1 7,  Methvin B Isaac 1
Affiliations

Affiliations

  • 1 Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario M5G 0A3, Canada.
  • 2 Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom.
  • 3 Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada.
  • 4 Reaction Biology Corp., Suite 2, 1 Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
  • 5 Charles River Discovery, Chesterford Research Park, Saffron Waldon, Essex CB10 1XL, United Kingdom.
  • 6 Charles River Discovery, 8-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
  • 7 M4K Pharma, 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.
  • 8 Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.
  • 9 Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences Building, Room 4207, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
PMID: 32787083 DOI: 10.1021/acs.jmedchem.0c01199
Abstract

There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric Cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease. We adopted an open science approach to develop a series of potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors based on the lead compound LDN-214117. Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds M4K2009, M4K2117, and M4K2163, each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust in vivo pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced preclinical compounds suitable for further development and evaluation in orthotopic models of DIPG.

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