7R60

BTK in complex with 18A

Summary for 7R60

• Entry DOI: 10.2210/pdb7r60/pdb
• Descriptor: Tyrosine-protein kinase BTK, 2-(4-phenoxyphenoxy)-5-[(3R)-1-(prop-2-enoyl)piperidin-3-yl]pyridine-3-carboxamide (3 entities in total)
• Functional Keywords: kinase, kinase inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 32043.80

Authors

Gardberg, A. (deposition date: 2021-06-22, release date: 2021-10-06, Last modification date: 2024-11-06)

Primary citation

Qiu, H.,Ali, Z.,Bowlan, J.,Caldwell, R.,Gardberg, A.,Glaser, N.,Goutopoulos, A.,Head, J.,Johnson, T.,Maurer, C.,Georgi, K.,Grenningloh, R.,Fang, Z.,Morandi, F.,Rohdich, F.,Schmidt, R.,Follis, A.V.,Sherer, B.
Discovery of Covalent Bruton's Tyrosine Kinase Inhibitors with Decreased CYP2C8 Inhibitory Activity.
Chemmedchem, 16:3653-3662, 2021

PubMed Abstract: Bruton's tyrosine kinase (BTK) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage. Evidence has shown that inhibition of BTK has clinical benefit for the treatment of a wide array of autoimmune and inflammatory diseases. Previously we reported the discovery of a novel nicotinamide selectivity pocket (SP) series of potent and selective covalent irreversible BTK inhibitors. The top molecule 1 of that series strongly inhibited CYP2C8 (IC =100 nM), which was attributed to the bridged linker group. However, our effort on the linker replacement turned out to be fruitless. With the study of the X-ray crystal structure of compound 1, we envisioned the opportunity of removal of this liability via transposition of the linker moiety in 1 from C6 to C5 position of the pyridine core. With this strategy, our optimization led to the discovery of a novel series, in which the top molecule 18 A displayed reduced CYP inhibitory activity and good potency. To further explore this new series, different warheads besides acrylamide, for example cyanamide, were also tested. However, this effort didn't lead to the discovery of molecules with better potency than 18 A. The loss of potency in those molecules could be related to the reduced reactivity of the warhead or reversible binding mode. Further profiling of 18 A disclosed that it had a strong hERG (human Ether-a-go-go Related Gene) inhibition, which could be related to the phenoxyphenyl group.

PubMed: 34582626
DOI: 10.1002/cmdc.202100453

Experimental method

X-RAY DIFFRACTION (1.94 Å)