ArticleMolecular cancer therapeutics2019
Phenotype-Based Screens with Conformation-Specific Inhibitors Reveal p38 Gamma and Delta as Targets for HCC Polypharmacology.
Article in Molecular cancer therapeutics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 21 citations in OpenAlex.
- p38γ and p38δ MAP kinases in inflammation.Biochemical Society transactions · 2026Review
- Endoplasmic reticulum stress sensor protein PERK in hepatic stellate cells promotes the progression of hepatocellular carcinoma via p38δ MAPK/IL-1β axis.Scientific reports · 2025Article
- Design and synthesis of 3,4-seco-lupane triterpene-tryptamine derivatives and revealing their anti-bladder cancer mechanisms by combining TCGA and transcriptomic approaches.Scientific reports · 2025Article
- A stress-responsive p38 signaling axis in choanoflagellates.RSC chemical biology · 2025Article
- ModulatingAging · 2024Article
- WNTinib is a multi-kinase inhibitor with specificity against β-catenin mutant hepatocellular carcinoma.Nature cancer · 2023Article
- The Multikinase Inhibitor AD80 Induces Mitotic Catastrophe and Autophagy in Pancreatic Cancer Cells.Cancers · 2023Article
- Review
- The promising therapeutic potentials of ginsenosides mediated through p38 MAPK signaling inhibition.Heliyon · 2021Review
- AD80, a multikinase inhibitor, exhibits antineoplastic effects in acute leukemia cellular models targeting the PI3K/STMN1 axis.Investigational new drugs · 2021Article
- Stress kinases in the development of liver steatosis and hepatocellular carcinoma.Molecular metabolism · 2021Review
- A Special View of What Was Almost Forgotten: p38δ MAPK.Cancers · 2021Review
- Article
- Multi-kinase targeted therapy as a promising treatment strategy for ovarian tumors expressing sfRon receptor.Genes & cancer · 2020Article
- An up-to-date overview of computational polypharmacology in modern drug discovery.Expert opinion on drug discovery · 2020Review
Corrections and comments
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Authors and funding
14 authors at 1 institution in 1 country.
Funding
Abstract
The approved kinase inhibitors for hepatocellular carcinoma (HCC) are not matched to specific mutations within tumors. This has presented a daunting challenge; without a clear target or mechanism, no straightforward path has existed to guide the development of improved therapies for HCC. Here, we combine phenotypic screens with a class of conformation-specific kinase inhibitors termed type II to identify a multikinase inhibitor, AD80, with antitumoral activity across a variety of HCC preclinical models, including mouse xenografts. Mass spectrometry profiling found a number of kinases as putative targets for AD80, including several receptor and cytoplasmic protein kinases. Among these, we found p38 gamma and delta as direct targets of AD80. Notably, a closely related analog of AD80 lacking p38δ/γ activity, but retaining several other off-target kinases, lost significant activity in several HCC models. Moreover, forced and sustained MKK6 → p38→ATF2 signaling led to a significant reduction of AD80 activity within HCC cell lines. Together with HCC survival data in The Cancer Genome Atlas and RNA-seq analysis, we suggest p38 delta and gamma as therapeutic targets in HCC and an "AD80 inhibition signature" as identifying those patients with best clinical outcomes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.