Pharmacokinetic Profile Evaluation of Novel Combretastatin Derivative, LASSBio-1920, as a Promising Colorectal Anticancer Agent

• Published in: Pharmaceutics Vol. 15; no. 4; p. 1282
• Main Authors: Guimarães, Celina de Jesus, Carneiro, Teiliane Rodrigues, Frederico, Marisa Jadna Silva, de Carvalho, Guilherme G C, Little, Matthew, Freire, Valder N, França, Victor L B, do Amaral, Daniel Nascimento, Guedes, Jéssica de Siqueira, Barreiro, Eliezer J, Lima, Lídia Moreira, Barros-Nepomuceno, Francisco W A, Pessoa, Claudia
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-04-2023; MDPI
• Subjects: Apoptosis; Cancer; Care and treatment; Cell cycle; Cell division; Cell-mediated cytotoxicity; Colorectal cancer; combretastatin; Comparative analysis; Cytotoxicity; Dosage and administration; EGFR binding; Enzyme inhibitors; Evaluation; Flow cytometry; Kinases; Metabolism; Morphology; PAMPA; Penicillin; pharmacokinetic; Pharmacokinetics; R&D; Reagents; Research & development; Sodium; Testing; tubulin; Brazil; Rio de Janeiro Brazil; St Louis Missouri; United States > US; tubulin; combretastatin; EGFR binding; PAMPA; pharmacokinetic
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics15041282

LASSBio-1920 was synthesized due to the poor solubility of its natural precursor, combretastatin A4 (CA4). The cytotoxic potential of the compound against human colorectal cancer cells (HCT-116) and non-small cell lung cancer cells (PC-9) was evaluated, yielding IC
values of 0.06 and 0.07 μM, respectively. Its mechanism of action was analyzed by microscopy and flow cytometry, where LASSBio-1920 was found to induce apoptosis. Molecular docking simulations and the enzymatic inhibition study with wild-type (wt) EGFR indicated enzyme-substrate interactions similar to other tyrosine kinase inhibitors. We suggest that LASSBio-1920 is metabolized by O-demethylation and NADPH generation. LASSBio-1920 demonstrated excellent absorption in the gastrointestinal tract and high central nervous system (CNS) permeability. The pharmacokinetic parameters obtained by predictions indicated that the compound presents zero-order kinetics and, in a human module simulation, accumulates in the liver, heart, gut, and spleen. The pharmacokinetic parameters obtained will serve as the basis to initiate in vivo studies regarding LASSBio-1920's antitumor potential.