A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability

Carolin Temps; Daniel  Leitha; Emily Webb; Xue-Feng Li; John C Dawson; Morwenna Muir; Kenneth Macleod; Teresa Valero; Alison Munro; Rafael Contreras-montoya; Juan R Luque-Ortega; Craig Fraser; Henry Beetham; Christina Schoenherr; Maria Lopalco; Mark J Arends; Margaret C Frame; Bin-Zhi Qian; Valerie G Brunton; Neil O Carragher; Asier Unciti-Broceta

doi:10.1158/0008-5472.CAN-21-0613

A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability

Carolin Temps, Daniel Leitha, Emily Webb, Xue-Feng Li, John C Dawson, Morwenna Muir, Kenneth Macleod, Teresa Valero, Alison Munro, Rafael Contreras-montoya, Juan R Luque-Ortega, Craig Fraser, Henry Beetham, Christina Schoenherr, Maria Lopalco, Mark J Arends, Margaret C Frame, Bin-Zhi Qian, Valerie G Brunton, Neil O CarragherAsier Unciti-Broceta

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

Abstract / Description of output

Despite the approval of several multikinase inhibitors that target SRC and the overwhelming evidence of the role of SRC in the progression and resistance mechanisms of many solid malignancies, inhibition of its kinase activity has thus far failed to improve patient outcomes. Here we report the small molecule eCF506 locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions that prevent phosphorylation and complex formation with its partner FAK. This unprecedented mechanism of action resulted in highly potent and selective pathway inhibition, in culture and in vivo. Treatment with eCF506 resulted in increased antitumor efficacy and tolerability in syngeneic murine cancer models, demonstrating significant therapeutic advantages over existing SRC/ABL inhibitors. Therefore, this novel mode of inhibiting SRC could lead to improved treatment of SRC-associated disorders.

Original language	English
Journal	Cancer Research
Early online date	20 Aug 2021
DOIs	https://doi.org/10.1158/0008-5472.CAN-21-0613
Publication status	E-pub ahead of print - 20 Aug 2021

Keywords / Materials (for Non-textual outputs)

SRC kinase
inactive conformation
kinase inhibitors
breast cancer
metastasis

Access to Document

10.1158/0008-5472.CAN-21-0613

A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and TolerabilityFinal published version, 1.32 MB

Wellcome Trust - ISSF3 Award
Cox, S.
1/03/20 → 1/03/21
Project: University Awarded Project Funding
The role of tumor microenvironment in metastatic hormone-refractory prostate cancer
Qian, B.
EU government bodies
1/04/17 → 30/09/22
Project: Research
The role(s) of macrophages in breast cancer bone metastas
Qian, B.
UK-based charities
1/03/15 → 28/02/21
Project: Research

Edinburgh Drug Discovery
Asier Unciti-Broceta (Manager), Scott Webster (Manager) & Neil Carragher (Manager)
Deanery of Molecular, Genetic and Population Health Sciences
Facility/equipment: Facility
Host and Tumour Profiling Unit (HTPU) Microarray Services
Alison Munro (Manager) & Kenneth Macleod (Other)
Deanery of Molecular, Genetic and Population Health Sciences
Facility/equipment: Facility

Cite this

Temps, C., Leitha, D., Webb, E., Li, X.-F., Dawson, J. C., Muir, M., Macleod, K., Valero, T., Munro, A., Contreras-montoya, R., Luque-Ortega, J. R., Fraser, C., Beetham, H., Schoenherr, C., Lopalco, M., Arends, M. J., Frame, M. C., Qian, B.-Z., Brunton, V. G., ... Unciti-Broceta, A. (2021). A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability. Cancer Research. Advance online publication. https://doi.org/10.1158/0008-5472.CAN-21-0613

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title = "A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability",

abstract = "Despite the approval of several multikinase inhibitors that target SRC and the overwhelming evidence of the role of SRC in the progression and resistance mechanisms of many solid malignancies, inhibition of its kinase activity has thus far failed to improve patient outcomes. Here we report the small molecule eCF506 locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions that prevent phosphorylation and complex formation with its partner FAK. This unprecedented mechanism of action resulted in highly potent and selective pathway inhibition, in culture and in vivo. Treatment with eCF506 resulted in increased antitumor efficacy and tolerability in syngeneic murine cancer models, demonstrating significant therapeutic advantages over existing SRC/ABL inhibitors. Therefore, this novel mode of inhibiting SRC could lead to improved treatment of SRC-associated disorders.",

keywords = "SRC kinase, inactive conformation, kinase inhibitors, breast cancer, metastasis",

author = "Carolin Temps and Daniel Leitha and Emily Webb and Xue-Feng Li and Dawson, {John C} and Morwenna Muir and Kenneth Macleod and Teresa Valero and Alison Munro and Rafael Contreras-montoya and Luque-Ortega, {Juan R} and Craig Fraser and Henry Beetham and Christina Schoenherr and Maria Lopalco and Arends, {Mark J} and Frame, {Margaret C} and Bin-Zhi Qian and Brunton, {Valerie G} and Carragher, {Neil O} and Asier Unciti-Broceta",

year = "2021",

month = aug,

day = "20",

doi = "10.1158/0008-5472.CAN-21-0613",

language = "English",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

}

Temps, C, Leitha, D, Webb, E, Li, X-F, Dawson, JC , Muir, M, Macleod, K, Valero, T, Munro, A, Contreras-montoya, R, Luque-Ortega, JR, Fraser, C, Beetham, H, Schoenherr, C, Lopalco, M, Arends, MJ , Frame, MC, Qian, B-Z, Brunton, VG , Carragher, NO & Unciti-Broceta, A 2021, 'A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability', Cancer Research. https://doi.org/10.1158/0008-5472.CAN-21-0613

TY - JOUR

T1 - A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability

AU - Temps, Carolin

AU - Leitha, Daniel

AU - Webb, Emily

AU - Li, Xue-Feng

AU - Dawson, John C

AU - Muir, Morwenna

AU - Macleod, Kenneth

AU - Valero, Teresa

AU - Munro, Alison

AU - Contreras-montoya, Rafael

AU - Luque-Ortega, Juan R

AU - Fraser, Craig

AU - Beetham, Henry

AU - Schoenherr, Christina

AU - Lopalco, Maria

AU - Arends, Mark J

AU - Frame, Margaret C

AU - Qian, Bin-Zhi

AU - Brunton, Valerie G

AU - Carragher, Neil O

AU - Unciti-Broceta, Asier

PY - 2021/8/20

Y1 - 2021/8/20

N2 - Despite the approval of several multikinase inhibitors that target SRC and the overwhelming evidence of the role of SRC in the progression and resistance mechanisms of many solid malignancies, inhibition of its kinase activity has thus far failed to improve patient outcomes. Here we report the small molecule eCF506 locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions that prevent phosphorylation and complex formation with its partner FAK. This unprecedented mechanism of action resulted in highly potent and selective pathway inhibition, in culture and in vivo. Treatment with eCF506 resulted in increased antitumor efficacy and tolerability in syngeneic murine cancer models, demonstrating significant therapeutic advantages over existing SRC/ABL inhibitors. Therefore, this novel mode of inhibiting SRC could lead to improved treatment of SRC-associated disorders.

AB - Despite the approval of several multikinase inhibitors that target SRC and the overwhelming evidence of the role of SRC in the progression and resistance mechanisms of many solid malignancies, inhibition of its kinase activity has thus far failed to improve patient outcomes. Here we report the small molecule eCF506 locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions that prevent phosphorylation and complex formation with its partner FAK. This unprecedented mechanism of action resulted in highly potent and selective pathway inhibition, in culture and in vivo. Treatment with eCF506 resulted in increased antitumor efficacy and tolerability in syngeneic murine cancer models, demonstrating significant therapeutic advantages over existing SRC/ABL inhibitors. Therefore, this novel mode of inhibiting SRC could lead to improved treatment of SRC-associated disorders.

KW - SRC kinase

KW - inactive conformation

KW - kinase inhibitors

KW - breast cancer

KW - metastasis

U2 - 10.1158/0008-5472.CAN-21-0613

DO - 10.1158/0008-5472.CAN-21-0613

M3 - Article

SN - 0008-5472

JO - Cancer Research

JF - Cancer Research

ER -

A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

Access to Document

Fingerprint

Projects

Wellcome Trust - ISSF3 Award

The role of tumor microenvironment in metastatic hormone-refractory prostate cancer

The role(s) of macrophages in breast cancer bone metastas

Equipment

Edinburgh Drug Discovery

Host and Tumour Profiling Unit (HTPU) Microarray Services

Cite this