Small-molecule IKKβ activation modulator (IKAM) targets MAP3K1 and inhibits pancreatic tumor growth-Reference-Cited by-同舟云学术

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

Published:2022-04-27 Issue:18 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Napoleon John Victor¹^ORCID,Sagar Satish¹,Kubica Sydney P.¹,Boghean Lidia¹^ORCID,Kour Smit¹^ORCID,King Hannah M.¹,Sonawane Yogesh A.¹,Crawford Ayrianne J.¹,Gautam Nagsen²,Kizhake Smitha¹^ORCID,Bialk Pawel A.³,Kmiec Eric³,Mallareddy Jayapal Reddy¹^ORCID,Patil Prathamesh P.¹^ORCID,Rana Sandeep¹,Singh Sarbjit¹,Prahlad Janani¹,Grandgenett Paul M.¹,Borgstahl Gloria E. O.¹^ORCID,Ghosal Gargi⁴^ORCID,Alnouti Yazen²,Hollingsworth Michael A.¹⁵,Radhakrishnan Prakash¹⁵^ORCID,Natarajan Amarnath¹²⁴⁵^ORCID

Affiliation:

1. Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198

2. Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198

3. Gene Editing Institute, Christiana Care, Newark, DE 19713

4. Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198

5. Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198

Abstract

Significance Pancreatic cancer is a deadly disease with limited therapeutic options. High expression of the kinase MAP3K1 is associated with poor survival among pancreatic cancer patients. MAP3K1 activates the kinase IKKβ, and our studies show that higher levels of activated IKKβ are found in patient-derived tumors as opposed to the surrounding normal tissue. We also show that inhibition of MAP3K1 by a drug-like compound 39-100 results in reduced levels of activated IKKβ. This leads to reduced tumor growth and reduced metastasis in pancreatic cancer models. Therefore, drug candidates like 39-100, that are IKKβ activation modulators, can be developed to treat pancreatic cancer.

Funder

HHS | National Institutes of Health

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2115071119

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