A small molecule inhibitor of HER3: a proof-of-concept study

Audrey Colomba; Martina Fitzek; Roger George; Gregory Weitsman; Selene Roberts; Laura Zanetti-Domingues; Michael Hirsch; Daniel J. Rolfe; Shahid Mehmood; Andrew Madin; Jeroen Claus; Svend Kjaer; Ambrosius P. Snijders; Tony Ng; Marisa Martin-Fernandez; David M. Smith; Peter J. Parker

doi:10.1042/BCJ20200496

A small molecule inhibitor of HER3: a proof-of-concept study

Audrey Colomba, Martina Fitzek, Roger George, Gregory Weitsman, Selene Roberts, Laura Zanetti-Domingues, Michael Hirsch, Daniel J. Rolfe, Shahid Mehmood, Andrew Madin, Jeroen Claus, Svend Kjaer, Ambrosius P. Snijders, Tony Ng, Marisa Martin-Fernandez, David M. Smith, Peter J. Parker

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

10 Citations (Scopus)

Abstract

Despite being catalytically defective, pseudokinases are typically essential players of cellular signalling, acting as allosteric regulators of their active counterparts. Deregulation of a growing number of pseudokinases has been linked to human diseases, making pseudokinases therapeutic targets of interest. Pseudokinases can be dynamic, adopting specific conformations critical for their allosteric function. Interfering with their allosteric role, with small molecules that would lock pseudokinases in a conformation preventing their productive partner interactions, is an attractive therapeutic strategy to explore. As a well-known allosteric activator of epidermal growth factor receptor family members, and playing a major part in cancer progression, the pseudokinase HER3 is a relevant context in which to address the potential of pseudokinases as drug targets for the development of allosteric inhibitors. In this proof-of-concept study, we developed a multiplex, medium-throughput thermal shift assay screening strategy to assess over 100 000 compounds and identify selective small molecule inhibitors that would trap HER3 in a conformation which is unfavourable for the formation of an active HER2-HER3 heterodimer. As a proof-of-concept compound, AC3573 bound with some specificity to HER3 and abrogated HER2-HER3 complex formation and downstream signalling in cells. Our study highlights the opportunity to identify new molecular mechanisms of action interfering with the biological function of pseudokinases.

Original language	English
Pages (from-to)	3329-3347
Number of pages	19
Journal	THE BIOCHEMICAL JOURNAL
Volume	477
Issue number	17
DOIs	https://doi.org/10.1042/BCJ20200496
Publication status	Published - 18 Sept 2020

Keywords

allostery
drug screening
HER3
inhibitor
pseudokinases

UN SDGs

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

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10.1042/BCJ20200496

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Colomba, A., Fitzek, M., George, R., Weitsman, G., Roberts, S., Zanetti-Domingues, L., Hirsch, M., Rolfe, D. J., Mehmood, S., Madin, A., Claus, J., Kjaer, S., Snijders, A. P., Ng, T., Martin-Fernandez, M., Smith, D. M., & Parker, P. J. (2020). A small molecule inhibitor of HER3: a proof-of-concept study. THE BIOCHEMICAL JOURNAL, 477(17), 3329-3347. https://doi.org/10.1042/BCJ20200496

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title = "A small molecule inhibitor of HER3: a proof-of-concept study",

abstract = "Despite being catalytically defective, pseudokinases are typically essential players of cellular signalling, acting as allosteric regulators of their active counterparts. Deregulation of a growing number of pseudokinases has been linked to human diseases, making pseudokinases therapeutic targets of interest. Pseudokinases can be dynamic, adopting specific conformations critical for their allosteric function. Interfering with their allosteric role, with small molecules that would lock pseudokinases in a conformation preventing their productive partner interactions, is an attractive therapeutic strategy to explore. As a well-known allosteric activator of epidermal growth factor receptor family members, and playing a major part in cancer progression, the pseudokinase HER3 is a relevant context in which to address the potential of pseudokinases as drug targets for the development of allosteric inhibitors. In this proof-of-concept study, we developed a multiplex, medium-throughput thermal shift assay screening strategy to assess over 100 000 compounds and identify selective small molecule inhibitors that would trap HER3 in a conformation which is unfavourable for the formation of an active HER2-HER3 heterodimer. As a proof-of-concept compound, AC3573 bound with some specificity to HER3 and abrogated HER2-HER3 complex formation and downstream signalling in cells. Our study highlights the opportunity to identify new molecular mechanisms of action interfering with the biological function of pseudokinases.",

keywords = "allostery, drug screening, HER3, inhibitor, pseudokinases",

author = "Audrey Colomba and Martina Fitzek and Roger George and Gregory Weitsman and Selene Roberts and Laura Zanetti-Domingues and Michael Hirsch and Rolfe, {Daniel J.} and Shahid Mehmood and Andrew Madin and Jeroen Claus and Svend Kjaer and Snijders, {Ambrosius P.} and Tony Ng and Marisa Martin-Fernandez and Smith, {David M.} and Parker, {Peter J.}",

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Colomba, A, Fitzek, M, George, R, Weitsman, G, Roberts, S, Zanetti-Domingues, L, Hirsch, M, Rolfe, DJ, Mehmood, S, Madin, A, Claus, J, Kjaer, S, Snijders, AP, Ng, T, Martin-Fernandez, M, Smith, DM & Parker, PJ 2020, 'A small molecule inhibitor of HER3: a proof-of-concept study', THE BIOCHEMICAL JOURNAL, vol. 477, no. 17, pp. 3329-3347. https://doi.org/10.1042/BCJ20200496

TY - JOUR

T1 - A small molecule inhibitor of HER3

T2 - a proof-of-concept study

AU - Colomba, Audrey

AU - Fitzek, Martina

AU - George, Roger

AU - Weitsman, Gregory

AU - Roberts, Selene

AU - Zanetti-Domingues, Laura

AU - Hirsch, Michael

AU - Rolfe, Daniel J.

AU - Mehmood, Shahid

AU - Madin, Andrew

AU - Claus, Jeroen

AU - Kjaer, Svend

AU - Snijders, Ambrosius P.

AU - Ng, Tony

AU - Martin-Fernandez, Marisa

AU - Smith, David M.

AU - Parker, Peter J.

PY - 2020/9/18

Y1 - 2020/9/18

N2 - Despite being catalytically defective, pseudokinases are typically essential players of cellular signalling, acting as allosteric regulators of their active counterparts. Deregulation of a growing number of pseudokinases has been linked to human diseases, making pseudokinases therapeutic targets of interest. Pseudokinases can be dynamic, adopting specific conformations critical for their allosteric function. Interfering with their allosteric role, with small molecules that would lock pseudokinases in a conformation preventing their productive partner interactions, is an attractive therapeutic strategy to explore. As a well-known allosteric activator of epidermal growth factor receptor family members, and playing a major part in cancer progression, the pseudokinase HER3 is a relevant context in which to address the potential of pseudokinases as drug targets for the development of allosteric inhibitors. In this proof-of-concept study, we developed a multiplex, medium-throughput thermal shift assay screening strategy to assess over 100 000 compounds and identify selective small molecule inhibitors that would trap HER3 in a conformation which is unfavourable for the formation of an active HER2-HER3 heterodimer. As a proof-of-concept compound, AC3573 bound with some specificity to HER3 and abrogated HER2-HER3 complex formation and downstream signalling in cells. Our study highlights the opportunity to identify new molecular mechanisms of action interfering with the biological function of pseudokinases.

AB - Despite being catalytically defective, pseudokinases are typically essential players of cellular signalling, acting as allosteric regulators of their active counterparts. Deregulation of a growing number of pseudokinases has been linked to human diseases, making pseudokinases therapeutic targets of interest. Pseudokinases can be dynamic, adopting specific conformations critical for their allosteric function. Interfering with their allosteric role, with small molecules that would lock pseudokinases in a conformation preventing their productive partner interactions, is an attractive therapeutic strategy to explore. As a well-known allosteric activator of epidermal growth factor receptor family members, and playing a major part in cancer progression, the pseudokinase HER3 is a relevant context in which to address the potential of pseudokinases as drug targets for the development of allosteric inhibitors. In this proof-of-concept study, we developed a multiplex, medium-throughput thermal shift assay screening strategy to assess over 100 000 compounds and identify selective small molecule inhibitors that would trap HER3 in a conformation which is unfavourable for the formation of an active HER2-HER3 heterodimer. As a proof-of-concept compound, AC3573 bound with some specificity to HER3 and abrogated HER2-HER3 complex formation and downstream signalling in cells. Our study highlights the opportunity to identify new molecular mechanisms of action interfering with the biological function of pseudokinases.

KW - allostery

KW - drug screening

KW - HER3

KW - inhibitor

KW - pseudokinases

UR - http://www.scopus.com/inward/record.url?scp=85091263566&partnerID=8YFLogxK

U2 - 10.1042/BCJ20200496

DO - 10.1042/BCJ20200496

M3 - Article

C2 - 32815546

AN - SCOPUS:85091263566

SN - 0264-6021

VL - 477

SP - 3329

EP - 3347

JO - THE BIOCHEMICAL JOURNAL

JF - THE BIOCHEMICAL JOURNAL

IS - 17

ER -

A small molecule inhibitor of HER3: a proof-of-concept study

Abstract

Keywords

UN SDGs

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