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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma

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Author(s):
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Ensan, Deeba [1, 2] ; Smil, David [2] ; Zepeda-Velazquez, Carlos A. [2] ; Panagopoulos, Dimitrios [3, 2, 4] ; Wong, Jong Fu [5] ; Williams, Eleanor P. [5] ; Adamson, Roslin [5] ; Bullock, Alex N. [5] ; Kiyota, Taira [2] ; Aman, Ahmed [2, 6] ; Roberts, Owen G. [7] ; Edwards, Aled M. [3, 7] ; O'Meara, Jeff A. [2] ; Isaac, Methvin B. [2] ; Al-awar, Rima [1, 2]
Total Authors: 15
Affiliation:
[1] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A8 - Canada
[2] Ontario Inst Canc Res, Drug Discovery Program, Toronto, ON M5G 0A3 - Canada
[3] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7 - Canada
[4] Simon Fraser Univ, Dept Chem, Columbia, BC V5A 1S6 - Canada
[5] Univ Oxford, Struct Genom Consortium, Oxford OX3 7DQ - England
[6] Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON M5S 3M2 - Canada
[7] M4K Pharma Inc, Toronto, ON M5G 1L7 - Canada
Total Affiliations: 7
Document type: Journal article
Source: Journal of Medicinal Chemistry; v. 63, n. 9, p. 4978-4996, MAY 14 2020.
Web of Science Citations: 0
Abstract

Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we adopted an open science approach to develop a series of potent type I inhibitors of ALK2 which are orally bio-available and brain-penetrant. Initial efforts resulted in the discovery of M4K2009, an analogue of the previously reported ALK2 inhibitor LDN-214117. Although highly selective for ALK2 over the TGF-beta R1 receptor ALK5, M4K2009 is also moderately active against the hERG potassium channel. Varying the substituents of the trimethoxyphenyl moiety gave rise to an equipotent benzamide analogue M4K2149 with reduced off-target affinity for the ion channel. Additional modifications yielded 2-fluoro-6-methoxybenzamide derivatives (26a-c), which possess high inhibitory activity against ALK2, excellent selectivity, and superior pharmacokinetic profiles. (AU)