Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its DMPK Profile

Raysa Magali Pillpe-Meza
ORCID logo ,
Wesley Leandro Gouveia
ORCID logo ,
Gisele Barbosa
ORCID logo ,
Carlos A. M. Fraga
ORCID logo ,
Eliezer J. Barreiro
ORCID logo ,
Lidia Moreira Lima
*
Version 1 : Received: 14 February 2024 / Approved: 15 February 2024 / Online: 15 February 2024 (15:35:47 CET)

A peer-reviewed article of this Preprint also exists.

Pillpe-Meza, R.M.; Gouveia, W.L.; Barbosa, G.; Fraga, C.A.M.; Barreiro, E.J.; Lima, L.M. Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile. Pharmaceuticals 2024, 17, 389. Pillpe-Meza, R.M.; Gouveia, W.L.; Barbosa, G.; Fraga, C.A.M.; Barreiro, E.J.; Lima, L.M. Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile. Pharmaceuticals 2024, 17, 389.

Abstract

Inappropriate expression of histone deacetylase (HDAC6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway are common aberrations observed in cancers. LASSBio-2208, was previously described as a dual inhibitor in the nanomolar range of HDAC6 and PI3Kα, being three times more potent in inhibiting HDAC-6. In this paper we described the cytotoxic and antiproliferative potency of LASSBio-2208 on different tumour cell lines, its possible synergism effect in association with PI3K and HDAC-6 inhibitors, and its DMPK in vitro profile. Our studies have demonstrated that LASSBio-2208 has moderate cytotoxic potency on MCF-7 (IC50 = 23 µM), CCRF-CEM (IC50 = 8.54 µM) and MOLT-4 (IC50 = 7.15 µM), with no cytotoxic effect on hPBMC. In addition, it has a good antiproliferative effect on MCF-7 cells (IC50 = 5.44 µM), low absorption by PAMPA-GIT and low permeation through the blood-brain barrier by PAMPA-BBB, exhibiting high metabolic stability in rat plasma. Moreover, LASSBio-2208 exhibited synergism when combined with getadolisib and tubastatin A, using the concentration corresponding to their CC50 values on MOLT-4 and CCRF-CEM cells.

Keywords

cancer; PI3K; HDAC6; cytotoxicity; antiproliferative; synergism; DMPK

Subject

Chemistry and Materials Science, Medicinal Chemistry

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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