Evidence map›Paper›PMID 40184776›Full record

ArticleEuropean journal of medicinal chemistry2025

Exploiting structural variability in the kinase back-pocket to modulate polypharmacology of TAM inhibitors.

Megan D Hopkins, Dehui Zhang, Zhilong Chen, Andrew L McIver, Justus M Huelse, Jyoti P Mahajan, Kaikai Lyu, Xiangbo Yang, Michael A Stashko, Brittany Smith and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in European journal of medicinal chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Megan D HopkinsCenter for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Dehui ZhangCenter for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Zhilong ChenCenter for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Andrew L McIverCenter for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Justus M HuelseAflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Jyoti P MahajanCenter for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Kaikai LyuCenter for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Xiangbo YangCenter for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Michael A StashkoCenter for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Brittany SmithAflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Tsz Y YeungAflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
H Shelton EarpDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Stephen V FryeCenter for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Deborah DeRyckereAflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Dmitri KireevCenter for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Douglas K GrahamAflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Xiaodong WangCenter for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. Electronic address: xiaodonw@unc.edu.

Funding

Research Training in Pediatric Non-Malignant HematologyT32HL139443 · NHLBI · EMORY UNIVERSITY · PI Clinton H Joiner, Shannon L. Meeks · 2018 to 2026
$2.6M
MERTK/AXL dual inhibitors provide novel treatment for cancer by targeting tumor cells and activating anti-tumor immunityR01CA249190 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI GRAHAM, DOUGLAS K, WANG, XIAODONG · 2020 to 2024
$2.5M
NCI NIH HHS R01 CA249190NHLBI NIH HHS T32 HL139443
6 · The paper itself

Abstract

TAM kinases play dual roles in tumor cells and the innate immune system. While they have redundant functions, the TAM kinases are differentially required in specific contexts. Therefore, inhibition of specific TAM kinases or pairs of TAM kinases will be desirable in different tumor types. We exploited the relatively more diversified back pocket of TAM kinases to modulate the polypharmacology of small molecule inhibitors and discovered several inhibitors with distinct selectivity profiles. The lead compound 45 (UNC8212) displayed potent inhibitory activities toward the TAM family. Its target engagement was confirmed by NanoBRET and cell-based assays. It also had favorable pharmacokinetic properties via intravenous and intraperitoneal routes.

Indexed as

PolypharmacologyProtein Kinase InhibitorsProtein-Tyrosine KinasesAnimalsDose-Response Relationship, DrugHumansMolecular StructureStructure-Activity RelationshipProtein Kinase InhibitorsProtein-Tyrosine Kinases

Identifiers

PMID40184776
PMCPMC12017460

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

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.