6I3U

Optimization of potent and selective ATM inhibitors suitable for a proof-of-concept study in Huntington's disease models

Summary for 6I3U

• Entry DOI: 10.2210/pdb6i3u/pdb
• Descriptor: Phosphatidylinositol 3-kinase catalytic subunit type 3, 2-morpholin-4-yl-6-[7-[(2~{R})-1-morpholin-4-ylpropan-2-yl]oxy-9~{H}-thioxanthen-4-yl]pyran-4-one (3 entities in total)
• Functional Keywords: atm surrogate, vps34, kinase, huntington's disease, lyase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 70641.74

Authors

Leonard, P.M. (deposition date: 2018-11-07, release date: 2019-03-20, Last modification date: 2024-01-24)

Primary citation

Toledo-Sherman, L.,Breccia, P.,Cachope, R.,Bate, J.R.,Angulo-Herrera, I.,Wishart, G.,Matthews, K.L.,Martin, S.L.,Cox, H.C.,McAllister, G.,Penrose, S.D.,Vater, H.,Esmieu, W.,Van de Poel, A.,Van de Bospoort, R.,Strijbosch, A.,Lamers, M.,Leonard, P.,Jarvis, R.E.,Blackaby, W.,Barnes, K.,Eznarriaga, M.,Dowler, S.,Smith, G.D.,Fischer, D.F.,Lazari, O.,Yates, D.,Rose, M.,Jang, S.W.,Munoz-Sanjuan, I.,Dominguez, C.
Optimization of Potent and Selective Ataxia Telangiectasia-Mutated Inhibitors Suitable for a Proof-of-Concept Study in Huntington's Disease Models.
J.Med.Chem., 62:2988-3008, 2019

PubMed Abstract: Genetic and pharmacological evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular and animal models of Huntington's disease (HD), suggesting that selective inhibition of ATM could provide a novel clinical intervention to treat HD. Here, we describe the development and characterization of ATM inhibitor molecules to enable in vivo proof-of-concept studies in HD animal models. Starting from previously reported ATM inhibitors, we aimed with few modifications to increase brain exposure by decreasing P-glycoprotein liability while maintaining potency and selectivity. Here, we report brain-penetrant ATM inhibitors that have robust pharmacodynamic (PD) effects consistent with ATM kinase inhibition in the mouse brain and an understandable pharmacokinetic/PD (PK/PD) relationship. Compound 17 engages ATM kinase and shows robust dose-dependent inhibition of X-ray irradiation-induced KAP1 phosphorylation in the mouse brain. Furthermore, compound 17 protects against mHTT (Q73)-induced cytotoxicity in a cortical-striatal cell model of HD.

PubMed: 30840447
DOI: 10.1021/acs.jmedchem.8b01819

Experimental method

X-RAY DIFFRACTION (2.09 Å)