4OTF

Crystal structure of the kinase domain of Bruton's Tyrosine kinase with GDC0834

Summary for 4OTF

• Entry DOI: 10.2210/pdb4otf/pdb
• Related: 3OCS 3OCT 3P03
• Descriptor: Tyrosine-protein kinase BTK, SULFATE ION, N-{3-[6-({4-[(2R)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl }-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide, ... (4 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q06187
• Total number of polymer chains: 1
• Total formula weight: 32617.37

Authors

Hymowitz, S.G.,Maurer, B. (deposition date: 2014-02-13, release date: 2015-01-28, Last modification date: 2023-12-06)

Primary citation

Young, W.B.,Barbosa, J.,Blomgren, P.,Bremer, M.C.,Crawford, J.J.,Dambach, D.,Gallion, S.,Hymowitz, S.G.,Kropf, J.E.,Lee, S.H.,Liu, L.,Lubach, J.W.,Macaluso, J.,Maciejewski, P.,Maurer, B.,Mitchell, S.A.,Ortwine, D.F.,Di Paolo, J.,Reif, K.,Scheerens, H.,Schmitt, A.,Sowell, C.G.,Wang, X.,Wong, H.,Xiong, J.M.,Xu, J.,Zhao, Z.,Currie, K.S.
Potent and selective Bruton's tyrosine kinase inhibitors: Discovery of GDC-0834.
Bioorg.Med.Chem.Lett., 25:1333-1337, 2015

PubMed Abstract: SAR studies focused on improving the pharmacokinetic (PK) properties of the previously reported potent and selective Btk inhibitor CGI-1746 (1) resulted in the clinical candidate GDC-0834 (2), which retained the potency and selectivity of CGI-1746, but with much improved PK in preclinical animal models. Structure based design efforts drove this work as modifications to 1 were investigated at both the solvent exposed region as well as 'H3 binding pocket'. However, in vitro metabolic evaluation of 2 revealed a non CYP-mediated metabolic process that was more prevalent in human than preclinical species (mouse, rat, dog, cyno), leading to a high-level of uncertainly in predicting human pharmacokinetics. Due to its promising potency, selectivity, and preclinical efficacy, a single dose IND was filed and 2 was taken in to a single dose phase I trial in healthy volunteers to quickly evaluate the human pharmacokinetics. In human, 2 was found to be highly labile at the exo-cyclic amide bond that links the tetrahydrobenzothiophene moiety to the central aniline ring, resulting in insufficient parent drug exposure. This information informed the back-up program and discovery of improved inhibitors.

PubMed: 25701252
DOI: 10.1016/j.bmcl.2015.01.032

Experimental method

X-RAY DIFFRACTION (1.95 Å)