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Targeted degradation of MERTK and other TAM receptor paralogs by heterobifunctional targeted protein degraders

TAM receptors (TYRO3, AXL, and MERTK) comprise a family of homologous receptor tyrosine kinases (RTK) that are expressed across a range of liquid and solid tumors where they contribute to both oncogenic signaling to promote tumor proliferation and survival, as well as expressed on myeloid and immune...

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Autores principales: Gadiyar, Varsha, Patel, Gopi, Chen, Jesse, Vigil, Dominico, Ji, Nan, Campbell, Veronica, Sharma, Kirti, Shi, Yatao, Weiss, Matthew M., Birge, Raymond B., Davra, Viralkumar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10397400/
https://www.ncbi.nlm.nih.gov/pubmed/37545504
http://dx.doi.org/10.3389/fimmu.2023.1135373
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author Gadiyar, Varsha
Patel, Gopi
Chen, Jesse
Vigil, Dominico
Ji, Nan
Campbell, Veronica
Sharma, Kirti
Shi, Yatao
Weiss, Matthew M.
Birge, Raymond B.
Davra, Viralkumar
author_facet Gadiyar, Varsha
Patel, Gopi
Chen, Jesse
Vigil, Dominico
Ji, Nan
Campbell, Veronica
Sharma, Kirti
Shi, Yatao
Weiss, Matthew M.
Birge, Raymond B.
Davra, Viralkumar
author_sort Gadiyar, Varsha
collection PubMed
description TAM receptors (TYRO3, AXL, and MERTK) comprise a family of homologous receptor tyrosine kinases (RTK) that are expressed across a range of liquid and solid tumors where they contribute to both oncogenic signaling to promote tumor proliferation and survival, as well as expressed on myeloid and immune cells where they function to suppress host anti-tumor immunity. In recent years, several strategies have been employed to inhibit TAM kinases, most notably small molecule tyrosine kinase inhibitors and inhibitory neutralizing monoclonal antibodies (mAbs) that block receptor dimerization. Targeted protein degraders (TPD) use the ubiquitin proteasome pathway to redirect E3 ubiquitin ligase activity and target specific proteins for degradation. Here we employ first-in-class TPDs specific for MERTK/TAMs that consist of a cereblon E3 ligase binder linked to a tyrosine kinase inhibitor targeting MERTK and/or AXL and TYRO3. A series of MERTK TPDs were designed and investigated for their capacity to selectively degrade MERTK chimeric receptors, reduce surface expression on primary efferocytic bone marrow-derived macrophages, and impact on functional reduction in efferocytosis (clearance of apoptotic cells). We demonstrate proof-of-concept and establish that TPDs can be tailored to either selectivity degrades MERTK or concurrently degrade multiple TAMs and modulate receptor expression in vitro and in vivo. This work demonstrates the utility of proteome editing, enabled by tool degraders developed here towards dissecting the therapeutically relevant pathway biology in preclinical models, and the ability for TPDs to degrade transmembrane proteins. These data also provide proof of concept that TPDs may serve as a viable therapeutic strategy for targeting MERTK and other TAMs and that this technology could be expanded to other therapeutically relevant transmembrane proteins.
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spelling pubmed-103974002023-08-04 Targeted degradation of MERTK and other TAM receptor paralogs by heterobifunctional targeted protein degraders Gadiyar, Varsha Patel, Gopi Chen, Jesse Vigil, Dominico Ji, Nan Campbell, Veronica Sharma, Kirti Shi, Yatao Weiss, Matthew M. Birge, Raymond B. Davra, Viralkumar Front Immunol Immunology TAM receptors (TYRO3, AXL, and MERTK) comprise a family of homologous receptor tyrosine kinases (RTK) that are expressed across a range of liquid and solid tumors where they contribute to both oncogenic signaling to promote tumor proliferation and survival, as well as expressed on myeloid and immune cells where they function to suppress host anti-tumor immunity. In recent years, several strategies have been employed to inhibit TAM kinases, most notably small molecule tyrosine kinase inhibitors and inhibitory neutralizing monoclonal antibodies (mAbs) that block receptor dimerization. Targeted protein degraders (TPD) use the ubiquitin proteasome pathway to redirect E3 ubiquitin ligase activity and target specific proteins for degradation. Here we employ first-in-class TPDs specific for MERTK/TAMs that consist of a cereblon E3 ligase binder linked to a tyrosine kinase inhibitor targeting MERTK and/or AXL and TYRO3. A series of MERTK TPDs were designed and investigated for their capacity to selectively degrade MERTK chimeric receptors, reduce surface expression on primary efferocytic bone marrow-derived macrophages, and impact on functional reduction in efferocytosis (clearance of apoptotic cells). We demonstrate proof-of-concept and establish that TPDs can be tailored to either selectivity degrades MERTK or concurrently degrade multiple TAMs and modulate receptor expression in vitro and in vivo. This work demonstrates the utility of proteome editing, enabled by tool degraders developed here towards dissecting the therapeutically relevant pathway biology in preclinical models, and the ability for TPDs to degrade transmembrane proteins. These data also provide proof of concept that TPDs may serve as a viable therapeutic strategy for targeting MERTK and other TAMs and that this technology could be expanded to other therapeutically relevant transmembrane proteins. Frontiers Media S.A. 2023-07-20 /pmc/articles/PMC10397400/ /pubmed/37545504 http://dx.doi.org/10.3389/fimmu.2023.1135373 Text en Copyright © 2023 Gadiyar, Patel, Chen, Vigil, Ji, Campbell, Sharma, Shi, Weiss, Birge and Davra https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Gadiyar, Varsha
Patel, Gopi
Chen, Jesse
Vigil, Dominico
Ji, Nan
Campbell, Veronica
Sharma, Kirti
Shi, Yatao
Weiss, Matthew M.
Birge, Raymond B.
Davra, Viralkumar
Targeted degradation of MERTK and other TAM receptor paralogs by heterobifunctional targeted protein degraders
title Targeted degradation of MERTK and other TAM receptor paralogs by heterobifunctional targeted protein degraders
title_full Targeted degradation of MERTK and other TAM receptor paralogs by heterobifunctional targeted protein degraders
title_fullStr Targeted degradation of MERTK and other TAM receptor paralogs by heterobifunctional targeted protein degraders
title_full_unstemmed Targeted degradation of MERTK and other TAM receptor paralogs by heterobifunctional targeted protein degraders
title_short Targeted degradation of MERTK and other TAM receptor paralogs by heterobifunctional targeted protein degraders
title_sort targeted degradation of mertk and other tam receptor paralogs by heterobifunctional targeted protein degraders
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10397400/
https://www.ncbi.nlm.nih.gov/pubmed/37545504
http://dx.doi.org/10.3389/fimmu.2023.1135373
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