6N9P

Discovery of affinity-based probes for Btk occupancy assay

Summary for 6N9P

• Entry DOI: 10.2210/pdb6n9p/pdb
• Descriptor: Tyrosine-protein kinase BTK, N-(3-{[2-amino-3-(4-phenoxyphenyl)pyridin-4-yl]oxy}phenyl)propanamide (3 entities in total)
• Functional Keywords: btk tool compound, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 32023.77

Authors

Mochalkin, I. (deposition date: 2018-12-03, release date: 2019-02-06, Last modification date: 2024-11-20)

Primary citation

Qiu, H.,Caldwell, R.,Liu-Bujalski, L.,Goutopoulos, A.,Jones, R.,Potnick, J.,Sherer, B.,Bender, A.,Grenningloh, R.,Xu, D.,Gardberg, A.,Mochalkin, I.,Johnson, T.,Viacava Follis, A.,Head, J.,Morandi, F.
Discovery of Affinity-Based Probes for Btk Occupancy Assays.
ChemMedChem, 14:217-223, 2019

PubMed Abstract: Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.

PubMed: 30521698
DOI: 10.1002/cmdc.201800714

Experimental method

X-RAY DIFFRACTION (2.23 Å)