posted on 2021-03-30, 14:36authored byAmanda Van de Poël, Leticia Toledo-Sherman, Perla Breccia, Roger Cachope, Jennifer R. Bate, Ivan Angulo-Herrera, Grant Wishart, Kim L. Matthews, Sarah L. Martin, Marcus Peacock, Amy Barnard, Helen C. Cox, Graham Jones, George McAllister, Huw Vater, William Esmieu, Cole Clissold, Marieke Lamers, Philip Leonard, Rebecca E. Jarvis, Wesley Blackaby, Maria Eznarriaga, Ovadia Lazari, Dawn Yates, Mark Rose, Sung-Wook Jang, Ignacio Muñoz-Sanjuan, Celia Dominguez
Our
group has recently shown that brain-penetrant ataxia telangiectasia-mutated
(ATM) kinase inhibitors may have potential as novel therapeutics for
the treatment of Huntington’s disease (HD). However, the previously
described pyranone-thioxanthenes (e.g., 4) failed to
afford selectivity over a vacuolar protein sorting 34 (Vps34) kinase,
an important kinase involved with autophagy. Given that impaired autophagy
has been proposed as a pathogenic mechanism of neurodegenerative diseases
such as HD, achieving selectivity over Vps34 became an important objective
for our program. Here, we report the successful selectivity optimization
of ATM over Vps34 by using X-ray crystal structures of a Vps34-ATM
protein chimera where the Vps34 ATP-binding site was mutated to approximate
that of an ATM kinase. The morpholino-pyridone and morpholino-pyrimidinone
series that resulted as a consequence of this selectivity optimization
process have high ATM potency and good oral bioavailability and have
lower molecular weight, reduced lipophilicity, higher aqueous solubility,
and greater synthetic tractability compared to the pyranone-thioxanthenes.