6DCG

Discovery of MK-8353: An Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology

6DCG の概要

• エントリーDOI: 10.2210/pdb6dcg/pdb
• 分子名称: Mitogen-activated protein kinase 1, SULFATE ION, (3S)-3-(methylsulfanyl)-1-(2-{4-[4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]-3,6-dihydropyridin-1(2H)-yl}-2-oxoethyl)-N-(3-{6-[(propan-2-yl)oxy]pyridin-3-yl}-1H-indazol-5-yl)pyrrolidine-3-carboxamide, ... (4 entities in total)
• 機能のキーワード: kinase inhibitor, kinase selectivity, transferase, serine/ threonine-protein kinase, map kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Rattus norvegicus (Rat)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43245.67

構造登録者

Boga, S.B.,Deng, Y.,Zhu, L.,Nan, Y.,Cooper, A.,Shipps Jr., G.W.,Doll, R.,Shih, N.,Zhu, H.,Sun, R.,Wang, T.,Paliwal, S.,Tsui, H.,Gao, X.,Yao, X.,Desai, J.,Wang, J.,Alhassan, A.B.,Kelly, J.,Patel, M.,Muppalla, K.,Gudipati, S.,Zhang, L.,Buevich, A.,Hesk, D.,Carr, D.,Dayananth, P.,Mei, H.,Cox, K.,Sherborne, B.,Hruza, A.W.,Xiao, L.,Jin, W.,Long, B.,Liu, G.,Taylor, S.A.,Kirschmeier, P.,Windsor, W.T.,Bishop, R.,Samatar, A.A. (登録日: 2018-05-06, 公開日: 2018-08-08, 最終更新日: 2023-10-11)

主引用文献

Boga, S.B.,Deng, Y.,Zhu, L.,Nan, Y.,Cooper, A.B.,Shipps Jr., G.W.,Doll, R.,Shih, N.Y.,Zhu, H.,Sun, R.,Wang, T.,Paliwal, S.,Tsui, H.C.,Gao, X.,Yao, X.,Desai, J.,Wang, J.,Alhassan, A.B.,Kelly, J.,Patel, M.,Muppalla, K.,Gudipati, S.,Zhang, L.K.,Buevich, A.,Hesk, D.,Carr, D.,Dayananth, P.,Black, S.,Mei, H.,Cox, K.,Sherborne, B.,Hruza, A.W.,Xiao, L.,Jin, W.,Long, B.,Liu, G.,Taylor, S.A.,Kirschmeier, P.,Windsor, W.T.,Bishop, R.,Samatar, A.A.
MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology.
ACS Med Chem Lett, 9:761-767, 2018

PubMed Abstract: The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound ) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3()-thiomethyl pyrrolidine analog . Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate suitable for twice daily oral dosing as a potential new cancer therapeutic.

PubMed: 30034615
DOI: 10.1021/acsmedchemlett.8b00220

実験手法

X-RAY DIFFRACTION (1.45 Å)