6DCG

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

Summary for 6DCG

• Entry DOI: 10.2210/pdb6dcg/pdb
• Descriptor: 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)
• Functional Keywords: kinase inhibitor, kinase selectivity, transferase, serine/ threonine-protein kinase, map kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Rattus norvegicus (Rat)
• Total number of polymer chains: 1
• Total formula weight: 43245.67

Authors

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. (deposition date: 2018-05-06, release date: 2018-08-08, Last modification date: 2023-10-11)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.45 Å)