6B16

P21-activated kinase 1 in complex with a 4-azaindole inhibitor

Summary for 6B16

• Entry DOI: 10.2210/pdb6b16/pdb
• Descriptor: Serine/threonine-protein kinase PAK 1, N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, inhibitor, complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q13153
• Total number of polymer chains: 2
• Total formula weight: 67963.99

Authors

Rouge, L.,Wang, W. (deposition date: 2017-09-16, release date: 2017-10-25, Last modification date: 2024-11-06)

Primary citation

Lee, W.,Crawford, J.J.,Aliagas, I.,Murray, L.J.,Tay, S.,Wang, W.,Heise, C.E.,Hoeflich, K.P.,La, H.,Mathieu, S.,Mintzer, R.,Ramaswamy, S.,Rouge, L.,Rudolph, J.
Synthesis and evaluation of a series of 4-azaindole-containing p21-activated kinase-1 inhibitors.
Bioorg. Med. Chem. Lett., 26:3518-3524, 2016

PubMed Abstract: A series of 4-azaindole-containing p21-activated kinase-1 (PAK1) inhibitors was prepared with the goal of improving physicochemical properties relative to an indole starting point. Indole 1 represented an attractive, non-basic scaffold with good PAK1 affinity and cellular potency but was compromised by high lipophilicity (clogD=4.4). Azaindole 5 was designed as an indole surrogate with the goal of lowering logD and resulted in equipotent PAK1 inhibition with a 2-fold improvement in cellular potency over 1. Structure-activity relationship studies around 5 identified additional 4-azaindole analogs with superior PAK1 biochemical activity (Ki <10nM) and up to 24-fold selectivity for group I over group II PAKs. Compounds from this series showed enhanced permeability, improved aqueous solubility, and lower plasma protein binding over indole 1. The improvement in physicochemical properties translated to a 20-fold decrease in unbound clearance in mouse PK studies for azaindole 5 relative to indole 1.

PubMed: 27346791
DOI: 10.1016/j.bmcl.2016.06.031

Experimental method

X-RAY DIFFRACTION (2.285 Å)