Héctor González-Álvarez, Deeba Ensan, Tao Xin, Jong Fu Wong, Carlos A Zepeda-Velázquez, Julien Cros, Laurent Hoffer, Taira Kiyota, Brian J Wilson, Ahmed Aman, Owen Roberts, Methvin B Isaac, Alex N Bullock, David Smil, Rima Al-Awar
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...
March 18, 2024: Journal of Medicinal Chemistry