6CPW

Discovery of 3(S)-thiomethyl pyrrolidine ERK inhibitors for oncology

Summary for 6CPW

• Entry DOI: 10.2210/pdb6cpw/pdb
• Descriptor: Mitogen-activated protein kinase 1, SULFATE ION, (3S)-N-[3-(4-fluorophenyl)-1H-indazol-5-yl]-3-(methylsulfanyl)-1-(2-oxo-2-{4-[4-(pyrimidin-2-yl)phenyl]piperazin-1-yl}ethyl)pyrrolidine-3-carboxamide, ... (4 entities in total)
• Functional Keywords: transferase, serine/threonine-protein kinase, map kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Rattus norvegicus (Rat)
• Cellular location: Cytoplasm, cytoskeleton, spindle : P63086
• Total number of polymer chains: 1
• Total formula weight: 43204.60

Authors

Hruza, A.,Hruza, A. (deposition date: 2018-03-14, release date: 2018-05-23, Last modification date: 2023-10-04)

Primary citation

Boga, S.B.,Alhassan, A.B.,Cooper, A.B.,Doll, R.,Shih, N.Y.,Shipps, G.,Deng, Y.,Zhu, H.,Nan, Y.,Sun, R.,Zhu, L.,Desai, J.,Patel, M.,Muppalla, K.,Gao, X.,Wang, J.,Yao, X.,Kelly, J.,Gudipati, S.,Paliwal, S.,Tsui, H.C.,Wang, T.,Sherborne, B.,Xiao, L.,Hruza, A.,Buevich, A.,Zhang, L.K.,Hesk, D.,Samatar, A.A.,Carr, D.,Long, B.,Black, S.,Dayananth, P.,Windsor, W.,Kirschmeier, P.,Bishop, R.
Discovery of 3(S)-thiomethyl pyrrolidine ERK inhibitors for oncology.
Bioorg. Med. Chem. Lett., 28:2029-2034, 2018

PubMed Abstract: Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100 nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10 mpk = 0 μM h; F% = 0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10 mpk = 26 μM h; F% = 70).

PubMed: 29748051
DOI: 10.1016/j.bmcl.2018.04.063

Experimental method

X-RAY DIFFRACTION (1.85 Å)