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Small-molecule IKKβ activation modulator (IKAM) targets MAP3K1 and inhibits pancreatic tumor growth

Activation of inhibitor of nuclear factor NF-κB kinase subunit-β (IKKβ), characterized by phosphorylation of activation loop serine residues 177 and 181, has been implicated in the early onset of cancer. On the other hand, tissue-specific IKKβ knockout in Kras mutation-driven mouse models stalled th...

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Autores principales: Napoleon, John Victor, Sagar, Satish, Kubica, Sydney P., Boghean, Lidia, Kour, Smit, King, Hannah M., Sonawane, Yogesh A., Crawford, Ayrianne J., Gautam, Nagsen, Kizhake, Smitha, Bialk, Pawel A., Kmiec, Eric, Mallareddy, Jayapal Reddy, Patil, Prathamesh P., Rana, Sandeep, Singh, Sarbjit, Prahlad, Janani, Grandgenett, Paul M., Borgstahl, Gloria E. O., Ghosal, Gargi, Alnouti, Yazen, Hollingsworth, Michael A., Radhakrishnan, Prakash, Natarajan, Amarnath
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9170026/
https://www.ncbi.nlm.nih.gov/pubmed/35476515
http://dx.doi.org/10.1073/pnas.2115071119
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author Napoleon, John Victor
Sagar, Satish
Kubica, Sydney P.
Boghean, Lidia
Kour, Smit
King, Hannah M.
Sonawane, Yogesh A.
Crawford, Ayrianne J.
Gautam, Nagsen
Kizhake, Smitha
Bialk, Pawel A.
Kmiec, Eric
Mallareddy, Jayapal Reddy
Patil, Prathamesh P.
Rana, Sandeep
Singh, Sarbjit
Prahlad, Janani
Grandgenett, Paul M.
Borgstahl, Gloria E. O.
Ghosal, Gargi
Alnouti, Yazen
Hollingsworth, Michael A.
Radhakrishnan, Prakash
Natarajan, Amarnath
author_facet Napoleon, John Victor
Sagar, Satish
Kubica, Sydney P.
Boghean, Lidia
Kour, Smit
King, Hannah M.
Sonawane, Yogesh A.
Crawford, Ayrianne J.
Gautam, Nagsen
Kizhake, Smitha
Bialk, Pawel A.
Kmiec, Eric
Mallareddy, Jayapal Reddy
Patil, Prathamesh P.
Rana, Sandeep
Singh, Sarbjit
Prahlad, Janani
Grandgenett, Paul M.
Borgstahl, Gloria E. O.
Ghosal, Gargi
Alnouti, Yazen
Hollingsworth, Michael A.
Radhakrishnan, Prakash
Natarajan, Amarnath
author_sort Napoleon, John Victor
collection PubMed
description Activation of inhibitor of nuclear factor NF-κB kinase subunit-β (IKKβ), characterized by phosphorylation of activation loop serine residues 177 and 181, has been implicated in the early onset of cancer. On the other hand, tissue-specific IKKβ knockout in Kras mutation-driven mouse models stalled the disease in the precancerous stage. In this study, we used cell line models, tumor growth studies, and patient samples to assess the role of IKKβ and its activation in cancer. We also conducted a hit-to-lead optimization study that led to the identification of 39-100 as a selective mitogen-activated protein kinase kinase kinase (MAP3K) 1 inhibitor. We show that IKKβ is not required for growth of Kras mutant pancreatic cancer (PC) cells but is critical for PC tumor growth in mice. We also observed elevated basal levels of activated IKKβ in PC cell lines, PC patient-derived tumors, and liver metastases, implicating it in disease onset and progression. Optimization of an ATP noncompetitive IKKβ inhibitor resulted in the identification of 39-100, an orally bioavailable inhibitor with improved potency and pharmacokinetic properties. The compound 39-100 did not inhibit IKKβ but inhibited the IKKβ kinase MAP3K1 with low-micromolar potency. MAP3K1-mediated IKKβ phosphorylation was inhibited by 39-100, thus we termed it IKKβ activation modulator (IKAM) 1. In PC models, IKAM-1 reduced activated IKKβ levels, inhibited tumor growth, and reduced metastasis. Our findings suggests that MAP3K1-mediated IKKβ activation contributes to KRAS mutation-associated PC growth and IKAM-1 is a viable pretherapeutic lead that targets this pathway.
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spelling pubmed-91700262022-10-27 Small-molecule IKKβ activation modulator (IKAM) targets MAP3K1 and inhibits pancreatic tumor growth Napoleon, John Victor Sagar, Satish Kubica, Sydney P. Boghean, Lidia Kour, Smit King, Hannah M. Sonawane, Yogesh A. Crawford, Ayrianne J. Gautam, Nagsen Kizhake, Smitha Bialk, Pawel A. Kmiec, Eric Mallareddy, Jayapal Reddy Patil, Prathamesh P. Rana, Sandeep Singh, Sarbjit Prahlad, Janani Grandgenett, Paul M. Borgstahl, Gloria E. O. Ghosal, Gargi Alnouti, Yazen Hollingsworth, Michael A. Radhakrishnan, Prakash Natarajan, Amarnath Proc Natl Acad Sci U S A Biological Sciences Activation of inhibitor of nuclear factor NF-κB kinase subunit-β (IKKβ), characterized by phosphorylation of activation loop serine residues 177 and 181, has been implicated in the early onset of cancer. On the other hand, tissue-specific IKKβ knockout in Kras mutation-driven mouse models stalled the disease in the precancerous stage. In this study, we used cell line models, tumor growth studies, and patient samples to assess the role of IKKβ and its activation in cancer. We also conducted a hit-to-lead optimization study that led to the identification of 39-100 as a selective mitogen-activated protein kinase kinase kinase (MAP3K) 1 inhibitor. We show that IKKβ is not required for growth of Kras mutant pancreatic cancer (PC) cells but is critical for PC tumor growth in mice. We also observed elevated basal levels of activated IKKβ in PC cell lines, PC patient-derived tumors, and liver metastases, implicating it in disease onset and progression. Optimization of an ATP noncompetitive IKKβ inhibitor resulted in the identification of 39-100, an orally bioavailable inhibitor with improved potency and pharmacokinetic properties. The compound 39-100 did not inhibit IKKβ but inhibited the IKKβ kinase MAP3K1 with low-micromolar potency. MAP3K1-mediated IKKβ phosphorylation was inhibited by 39-100, thus we termed it IKKβ activation modulator (IKAM) 1. In PC models, IKAM-1 reduced activated IKKβ levels, inhibited tumor growth, and reduced metastasis. Our findings suggests that MAP3K1-mediated IKKβ activation contributes to KRAS mutation-associated PC growth and IKAM-1 is a viable pretherapeutic lead that targets this pathway. National Academy of Sciences 2022-04-27 2022-05-03 /pmc/articles/PMC9170026/ /pubmed/35476515 http://dx.doi.org/10.1073/pnas.2115071119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Napoleon, John Victor
Sagar, Satish
Kubica, Sydney P.
Boghean, Lidia
Kour, Smit
King, Hannah M.
Sonawane, Yogesh A.
Crawford, Ayrianne J.
Gautam, Nagsen
Kizhake, Smitha
Bialk, Pawel A.
Kmiec, Eric
Mallareddy, Jayapal Reddy
Patil, Prathamesh P.
Rana, Sandeep
Singh, Sarbjit
Prahlad, Janani
Grandgenett, Paul M.
Borgstahl, Gloria E. O.
Ghosal, Gargi
Alnouti, Yazen
Hollingsworth, Michael A.
Radhakrishnan, Prakash
Natarajan, Amarnath
Small-molecule IKKβ activation modulator (IKAM) targets MAP3K1 and inhibits pancreatic tumor growth
title Small-molecule IKKβ activation modulator (IKAM) targets MAP3K1 and inhibits pancreatic tumor growth
title_full Small-molecule IKKβ activation modulator (IKAM) targets MAP3K1 and inhibits pancreatic tumor growth
title_fullStr Small-molecule IKKβ activation modulator (IKAM) targets MAP3K1 and inhibits pancreatic tumor growth
title_full_unstemmed Small-molecule IKKβ activation modulator (IKAM) targets MAP3K1 and inhibits pancreatic tumor growth
title_short Small-molecule IKKβ activation modulator (IKAM) targets MAP3K1 and inhibits pancreatic tumor growth
title_sort small-molecule ikkβ activation modulator (ikam) targets map3k1 and inhibits pancreatic tumor growth
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9170026/
https://www.ncbi.nlm.nih.gov/pubmed/35476515
http://dx.doi.org/10.1073/pnas.2115071119
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