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

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 5) 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(S)-thiomethyl pyrrolidine analog 7. Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.

SUBMITTER: Boga SB 

PROVIDER: S-EPMC6047169 | biostudies-other | 2018 Jul

REPOSITORIES: biostudies-other

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

Boga Sobhana Babu SB   Deng Yongqi Y   Zhu Liang L   Nan Yang Y   Cooper Alan B AB   Shipps Gerald W GW   Doll Ronald R   Shih Neng-Yang NY   Zhu Hugh H   Sun Robert R   Wang Tong T   Paliwal Sunil S   Tsui Hon-Chung HC   Gao Xiaolei X   Yao Xin X   Desai Jagdish J   Wang James J   Alhassan Abdul Basit AB   Kelly Joseph J   Patel Mehul M   Muppalla Kiran K   Gudipati Subrahmanyam S   Zhang Li-Kang LK   Buevich Alexei A   Hesk David D   Carr Donna D   Dayananth Priya P   Black Stuart S   Mei Hong H   Cox Kathleen K   Sherborne Bradley B   Hruza Alan W AW   Xiao Li L   Jin Weihong W   Long Brian B   Liu Gongjie G   Taylor Stacey A SA   Kirschmeier Paul P   Windsor William T WT   Bishop Robert R   Samatar Ahmed A AA  

ACS medicinal chemistry letters 20180614 7

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 <b>5</b>) 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(<i>S</i>)-thiomethyl pyrrolidine analog <b>7</b>.  ...[more]

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