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 〖BTK〗^Cys481 Waldenström Macroglobulinemia: A computational Approach

Ghazi Elamin; Aimen Aljoundi; Mohamed Alahmdi; Nader E Abo-Dya; Mahmoud Soliman

doi:10.2174/1871520623666230208102609

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 〖BTK〗^Cys481 Waldenström Macroglobulinemia: A computational Approach

Anticancer Agents Med Chem. 2023 Feb 8. doi: 10.2174/1871520623666230208102609. Online ahead of print.

Authors

Ghazi Elamin¹, Aimen Aljoundi², Mohamed Alahmdi³, Nader E Abo-Dya⁴, Mahmoud Soliman⁵

Affiliations

¹ University of KwaZulu-Natal Pharmaceutical chemistry Durban South Africa.
² University of KwaZulu-Natal Pharmaceutical Chemistry Durban South Africa.
³ University of Tabuk Department of Chemistry Tabuk Saudi Arabia.
⁴ University of Tabuk Department of Pharmaceutical Chemistry Tabuk Saudi Arabia.
⁵ University of KwaZulu-Natal Pharmaceutical Sciences Durban South Africa.

PMID: 36752293
DOI: 10.2174/1871520623666230208102609

Abstract

Background: Despite 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.

Objective: Recently, 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.

Methods: Conducting predictive pharmacokinetic profiling of KIN-8194, as well as demonstrating a comparative structural mechanism of inhibition against the above-mentioned enzymes.

Results: Our 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.

Conclusion: These 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.

Keywords: BTK; HCK.; KIN-8194; Waldenström macroglobulinemia; dual-target; single-target.