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

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

doi:10.1021/acsmedchemlett.8b00220

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

Sobhana Babu Boga
, Yongqi Deng
, Liang Zhu
, Yang Nan
, Alan B. Cooper
, Gerald W. Shipps
, Ronald Doll
, Neng Yang Shih
, Hugh Zhu
, Robert Sun
, Tong Wang
, Sunil Paliwal
, Hon Chung Tsui
, Xiaolei Gao
, Xin Yao
, Jagdish Desai
, James Wang
, Abdul Basit Alhassan
, Joseph Kelly
, Mehul Patel

Kiran Muppalla, Subrahmanyam Gudipati, Li Kang Zhang, Alexei Buevich, David Hesk, Donna Carr, Priya Dayananth, Stuart Black, Hong Mei, Kathleen Cox, Bradley Sherborne, Alan W. Hruza, Li Xiao, Weihong Jin, Brian Long, Gongjie Liu, Stacey A. Taylor, Paul Kirschmeier, William T. Windsor, Robert Bishop, Ahmed A. Samatar

Department of Chemistry and Chemical Biology

Merck

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

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.

Original language	English
Pages (from-to)	761-767
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	9
Issue number	7
DOIs	https://doi.org/10.1021/acsmedchemlett.8b00220
State	Published - 12 Jul 2018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

ERK inhibitor
MAPK pathway
MK-8353
kinase selectivity
lead optimization
oncology

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10.1021/acsmedchemlett.8b00220

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Boga, S. B., Deng, Y., Zhu, L., Nan, Y., Cooper, A. B., Shipps, 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., ... Samatar, A. A. (2018). MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology. ACS Medicinal Chemistry Letters, 9(7), 761-767. https://doi.org/10.1021/acsmedchemlett.8b00220

@article{17f9b827d7a245b1beb4f17f91502a1d,

title = "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.",

keywords = "ERK inhibitor, MAPK pathway, MK-8353, kinase selectivity, lead optimization, oncology",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2018 American Chemical Society.",

year = "2018",

month = jul,

day = "12",

doi = "10.1021/acsmedchemlett.8b00220",

language = "English",

volume = "9",

pages = "761--767",

number = "7",

}

Boga, SB, Deng, Y, Zhu, L, Nan, Y, Cooper, AB, Shipps, GW, Doll, R, Shih, NY, Zhu, H, Sun, R, Wang, T, Paliwal, S, Tsui, HC, Gao, X, Yao, X, Desai, J, Wang, J, Alhassan, AB, Kelly, J, Patel, M, Muppalla, K, Gudipati, S, Zhang, LK, Buevich, A, Hesk, D, Carr, D, Dayananth, P, Black, S, Mei, H, Cox, K, Sherborne, B, Hruza, AW, Xiao, L, Jin, W, Long, B, Liu, G, Taylor, SA, Kirschmeier, P, Windsor, WT, Bishop, R & Samatar, AA 2018, 'MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology', ACS Medicinal Chemistry Letters, vol. 9, no. 7, pp. 761-767. https://doi.org/10.1021/acsmedchemlett.8b00220

TY - JOUR

T1 - MK-8353

T2 - Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology

AU - Boga, Sobhana Babu

AU - Deng, Yongqi

AU - Zhu, Liang

AU - Nan, Yang

AU - Cooper, Alan B.

AU - Shipps, Gerald W.

AU - Doll, Ronald

AU - Shih, Neng Yang

AU - Zhu, Hugh

AU - Sun, Robert

AU - Wang, Tong

AU - Paliwal, Sunil

AU - Tsui, Hon Chung

AU - Gao, Xiaolei

AU - Yao, Xin

AU - Desai, Jagdish

AU - Wang, James

AU - Alhassan, Abdul Basit

AU - Kelly, Joseph

AU - Patel, Mehul

AU - Muppalla, Kiran

AU - Gudipati, Subrahmanyam

AU - Zhang, Li Kang

AU - Buevich, Alexei

AU - Hesk, David

AU - Carr, Donna

AU - Dayananth, Priya

AU - Black, Stuart

AU - Mei, Hong

AU - Cox, Kathleen

AU - Sherborne, Bradley

AU - Hruza, Alan W.

AU - Xiao, Li

AU - Jin, Weihong

AU - Long, Brian

AU - Liu, Gongjie

AU - Taylor, Stacey A.

AU - Kirschmeier, Paul

AU - Windsor, William T.

AU - Bishop, Robert

AU - Samatar, Ahmed A.

PY - 2018/7/12

Y1 - 2018/7/12

N2 - 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.

AB - 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.

KW - ERK inhibitor

KW - MAPK pathway

KW - MK-8353

KW - kinase selectivity

KW - lead optimization

KW - oncology

UR - https://www.scopus.com/pages/publications/85048710639

UR - https://www.scopus.com/pages/publications/85048710639#tab=citedBy

U2 - 10.1021/acsmedchemlett.8b00220

DO - 10.1021/acsmedchemlett.8b00220

M3 - Article

AN - SCOPUS:85048710639

VL - 9

SP - 761

EP - 767

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 7

ER -

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

Abstract

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Keywords

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