5V9P

Crystal structure of pyrrolidine amide inhibitor [(3S)-3-(4-bromo-1H-pyrazol-1-yl)pyrrolidin-1-yl][3-(propan-2-yl)-1H-pyrazol-5-yl]methanone (compound 35) in complex with KDM5A

Summary for 5V9P

• Entry DOI: 10.2210/pdb5v9p/pdb
• Related: 5CEH 5V9T
• Descriptor: Lysine-specific demethylase 5A, NICKEL (II) ION, ZINC ION, ... (7 entities in total)
• Functional Keywords: epigenetics, histone demethylase, cancer, inhibitor, selective, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus, nucleolus : P29375
• Total number of polymer chains: 2
• Total formula weight: 92210.80

Authors

Kiefer, J.R.,Liang, J.,Vinogradova, M. (deposition date: 2017-03-23, release date: 2017-05-10, Last modification date: 2023-10-04)

Primary citation

Liang, J.,Labadie, S.,Zhang, B.,Ortwine, D.F.,Patel, S.,Vinogradova, M.,Kiefer, J.R.,Mauer, T.,Gehling, V.S.,Harmange, J.C.,Cummings, R.,Lai, T.,Liao, J.,Zheng, X.,Liu, Y.,Gustafson, A.,Van der Porten, E.,Mao, W.,Liederer, B.M.,Deshmukh, G.,An, L.,Ran, Y.,Classon, M.,Trojer, P.,Dragovich, P.S.,Murray, L.
From a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors.
Bioorg. Med. Chem. Lett., 27:2974-2981, 2017

PubMed Abstract: A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (LogD) compared with the original hit. Furthermore, 50 showed lower clearance than 9 in mice. In combination with its remarkably low plasma protein binding (PPB) in mice (40%), oral dosing of 50 at 5mg/kg resulted in unbound C ∼2-fold of its cell potency (PC9 H3K4Me3 0.96μM), meeting our criteria for an in vivo tool compound from a new scaffold.

PubMed: 28512031
DOI: 10.1016/j.bmcl.2017.05.016

Experimental method

X-RAY DIFFRACTION (3 Å)