ArticleAnti-cancer agents in medicinal chemistry2024
Revealing the Role of the Arg and Lys in Shifting Paradigm from BTK Selective Inhibition to the BTK/HCK Dual Inhibition - Delving into the Inhibitory Activity of KIN-8194 against BTK, and HCK in the Treatment of Mutated
Article in Anti-cancer agents in medicinal chemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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.
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.
Who cites it
2 citing papers in PubMed, 4 citations in OpenAlex.
- 7-O-methylpunctatin is a potential inhibitor of human arachidonate 5-lipoxygenase: molecular and structural insights into anti-atherosclerosis therapeutics.Molecular diversity · 2026Article
- In Silico Investigation of Phytochemicals From Clinically Tested Herbal Extracts as Potential Dihydrofolate Reductase Inhibitors for Buruli Ulcer.BioMed research international · 2025Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 2 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundDespite the early success of Bruton's tyrosine kinase (BTK) inhibitors in the treatment of Waldenström macroglobulinemia (WM), these single-target drug therapies have limitations in their clinical applications, such as drug resistance. Several alternative strategies have been developed, including the use of dual inhibitors, to maximize the therapeutic potential of these drugs.
objectiveRecently, the pharmacological activity of KIN-8194 was repurposed to serve as a 'dual-target' inhibitor of BTK and Hematopoietic Cell Kinase (HCK). However, the structural dual inhibitory mechanism remains unexplored, hence the aim of this study.
methodsConducting predictive pharmacokinetic profiling of KIN-8194, as well as demonstrating a comparative structural mechanism of inhibition against the above-mentioned enzymes.
resultsOur results revealed favourable binding affinities of -20.17 kcal/mol, and -35.82 kcal/mol for KIN-8194 towards HCK and BTK, respectively. Catalytic residues Arg137/174 and Lys42/170 in BTK and Arg303 and Lys75/173/244/247 in HCK were identified as crucial mediators of the dual binding mechanism of KIN-8194, corroborated by high per-residue energy contributions and consistent high-affinity interactions of these residues. Prediction of the pharmacokinetics and physicochemical properties of KIN-8194 further established its inhibitory potential, evidenced by the favourable absorption, metabolism, excretion, and minimal toxicity properties. Structurally, KIN-8194 impacted the stability, flexibility, solvent-accessible surface area, and rigidity of BTK and HCK, characterized by various alterations observed in the bound and unbound structures, which proved enough to disrupt their biological function.
conclusionThese structural insights provided a baseline for the understanding of the dual inhibitory activity of KIN- 8194. Establishing the cruciality of the interactions between the KIN-8194 and Arg and Lys residues could guide the structure-based design of novel dual BTK/HCK inhibitors with improved therapeutic activities.
Indexed as
Identifiers
What OpenQuestion holds
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.