2. Academic Validation
  3. Discovery of Conformationally Constrained ALK2 Inhibitors

Discovery of Conformationally Constrained ALK2 Inhibitors

  • J Med Chem. 2024 Mar 28;67(6):4707-4725. doi: 10.1021/acs.jmedchem.3c02308.
Héctor González-Álvarez 1 2,  Deeba Ensan 1 2,  Tao Xin 1,  Jong Fu Wong 3,  Carlos A Zepeda-Velázquez 1,  Julien Cros 4,  Melissa N Sweeney 4,  Laurent Hoffer 1,  Taira Kiyota 1,  Brian J Wilson 1,  Ahmed Aman 1 5,  Owen Roberts 6,  Methvin B Isaac 1,  Alex N Bullock 4,  David Smil 1,  Rima Al-Awar 1 2 7
Affiliations

Affiliations

  • 1 Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario M5G 0A3, Canada.
  • 2 Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences Building, Room 4207, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
  • 3 Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K.
  • 4 Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7FZ, U.K.
  • 5 Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada.
  • 6 M4K Pharma, 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.
  • 7 Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
PMID: 38498998 DOI: 10.1021/acs.jmedchem.3c02308
Abstract

Despite decades of research on new diffuse intrinsic pontine glioma (DIPG) treatments, little or no progress has been made on improving patient outcomes. In this work, we explored novel scaffold modifications of M4K2009, a 3,5-diphenylpyridine ALK2 Inhibitor previously reported by our group. Here we disclose the design, synthesis, and evaluation of a first-in-class set of 5- to 7-membered ether-linked and 7-membered amine-linked constrained inhibitors of ALK2. This rigidification strategy led us to the discovery of the ether-linked inhibitors M4K2308 and M4K2281 and the amine-linked inhibitors M4K2304 and M4K2306, each with superior potency against ALK2. Notably, M4K2304 and M4K2306 exhibit exceptional selectivity for ALK2 over ALK5, surpassing the reference compound. Preliminary studies on their in vivo pharmacokinetics, including blood-brain barrier penetration, revealed that these constrained scaffolds have favorable exposure and do open a novel chemical space for further optimization and future evaluation in orthotopic models of DIPG.

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