MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology PMID: 30034615

ADC Targets in Oncology

2026-04-10

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

ACS Med Chem Lett. 2018 Jun 14;9(7):761-767. doi: 10.1021/acsmedchemlett.8b00220.

Sobhana Babu Boga ¹ , Yongqi Deng ² , Liang Zhu ² , Yang Nan ² , Alan B Cooper ¹ , Gerald W Shipps Jr ² , Ronald Doll ¹ , Neng-Yang Shih ¹ , Hugh Zhu ¹ , Robert Sun ¹ , Tong Wang ² , Sunil Paliwal ¹ , Hon-Chung Tsui ¹ , Xiaolei Gao ¹ , Xin Yao ¹ , Jagdish Desai ¹ , James Wang ¹ , Abdul Basit Alhassan ¹ , Joseph Kelly ¹ , Mehul Patel ² , Kiran Muppalla ² , Subrahmanyam Gudipati ¹ , Li-Kang Zhang ¹ , Alexei Buevich ¹ , David Hesk ¹ , Donna Carr ¹ , Priya Dayananth ¹ , Stuart Black ¹ , Hong Mei ¹ , Kathleen Cox ¹ , Bradley Sherborne ¹ , Alan W Hruza ¹ , Li Xiao ¹ , Weihong Jin ¹ , Brian Long ¹ , Gongjie Liu ¹ , Stacey A Taylor ¹ , Paul Kirschmeier ¹ , William T Windsor ¹ , Robert Bishop ¹ , Ahmed A Samatar ¹

Affiliations

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.