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

David Smil | Zendy; Jong Fu Wong | Zendy; Eleanor Williams | Zendy; R.J. Adamson | Zendy; Alison Howarth | Zendy; David McLeod | Zendy; Ahmed Mamai | Zendy; Soyoung Kim | Zendy; Brian J. Wilson | Zendy; Taira Kiyota | Zendy; Ahmed Aman | Zendy; Julie Owen | Zendy; Gennady Poda | Zendy; Kurumi Y. Horiuchi | Zendy; Ekaterina Kuznetsova | Zendy; Haiching Ma | Zendy; J. Hamblin | Zendy; Sue Cramp | Zendy; Owen G Roberts | Zendy; A.M. Edwards | Zendy; David Uehling | Zendy; Rima Alawar | Zendy; Alex N. Bullock | Zendy; Jeff A. O’Meara | Zendy; Methvin Isaac | Zendy

Open Access

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

Author(s) -

David Smil,

Jong Fu Wong,

Eleanor Williams,

R.J. Adamson,

Alison Howarth,

David McLeod,

Ahmed Mamai,

Soyoung Kim,

Brian J. Wilson,

Taira Kiyota,

Ahmed Aman,

Julie Owen,

Gennady Poda,

Kurumi Y. Horiuchi,

Ekaterina Kuznetsova,

Haiching Ma,

J. Hamblin,

Sue Cramp,

Owen G Roberts,

A.M. Edwards,

David Uehling,

Rima Alawar,

Alex N. Bullock,

Jeff A. O’Meara,

Methvin Isaac

Publication year - 2020

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/acs.jmedchem.0c01199

Subject(s) - chemistry , drug discovery , pharmacology , pharmacokinetics , activin receptor , penetrant (biochemical) , blood–brain barrier , tolerability , cancer research , kinase , medicine , central nervous system , adverse effect , biochemistry , organic chemistry

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. Robus 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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