Evidence map›Paper›PMID 34176062›Full record

ArticleJournal of biomolecular NMR2021

Antipsychotic phenothiazine drugs bind to KRAS in vitro.

Xu Wang, Alemayehu A Gorfe, John A Putkey

Abstract read
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In one paragraph

Article in Journal of biomolecular NMR, 2021. 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
0.2field-weighted citation impact, top 47% of its field
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, 4 citations in OpenAlex.

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

3 authors at 2 institutions in 1 country.

Xu WangDepartment of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX, 77030, USA.
Alemayehu A GorfeDepartment of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX, 77030, USA.
John A PutkeyDepartment of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX, 77030, USA. john.putkey@uth.tmc.edu.ORCID http://orcid.org/0000-0002-8060-1281
The University of Texas Health Science Center · USThe University of Texas Health Science Center at Houston · US

Funding

Cancer Prevention and Research Institute of Texas DP150093
6 · The paper itself

Abstract

We used NMR to show that the antipsychotic phenothiazine drugs promazine and promethazine bind to GDP-KRAS. Promazine also binds to oncogenic GDP-KRAS(G12D), and to wild type GppNHp-KRAS. A panel of additional phenothiazines bind to GDP-KRAS but with lower affinity than promazine or promethazine. Binding is most dependent on substitutions at C-2 of the tricyclic phenothiazine ring. Promazine was used to generate an NMR-driven HADDOCK model of the drug/GDP-KRAS complex. The structural model shows the tricyclic phenothiazine ring of promazine associates with the hydrophobic pocket p1 that is bordered by the central β sheet and Switch II in KRAS. Binding appears to stabilize helix 2 in a conformation that is similar to that seen in KRAS bound to other small molecules. Association of phenothiazines with KRAS may affect normal KRAS signaling that could contribute to multiple biological activities of these antipsychotic drugs. Moreover, the phenothiazine ring represents a new core scaffold on which to design modulators of KRAS activity.

Indexed as

Models, MolecularAmino Acid SubstitutionAntipsychotic AgentsHumansMutation, MissenseNuclear Magnetic Resonance, BiomolecularPhenothiazinesProtein BindingProtein Conformation, beta-StrandProto-Oncogene Proteins p21(ras)Antipsychotic AgentsKRAS protein, humanphenothiazinePhenothiazinesProto-Oncogene Proteins p21(ras)Drug bindingNMRPhenothiazinesRasStructure activity relationship (SAR)

Identifiers

PMID34176062
OpenAlexW3176590726

What OpenQuestion holds

Textmetadata
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.