Conjugates Derived from Lapatinib Derivatives with Cancer Cell Stemness Inhibitors Effectively Reversed Drug Resistance in Triple-Negative Breast Cancer.

Increasing evidence indicates that the cancer stem cell (CSC) subpopulation contributes to the therapeutic resistance and metastasis of tumors, leading to patient recurrence and death. Herein, we designed and synthesized several compounds by conjugating lapatinib derivatives with different CSC inhibitors to treat with lapatinib-induced MDA-MB-231 drug-resistant cells. In vitro biological studies indicated that 3a showed strong cytotoxicity and EGFR enzyme inhibitory activity and effectively reversed lapatinib-mediated resistance of MDA-MB-231 cells via inhibiting triple-negative breast cancer (TNBC) cell stemness and the AKT/ERK signaling pathway. In addition, 3a was capable of strongly suppressing the invasion and migration of TNBC cells by inhibiting the Wnt/ß-catenin signaling pathway and MMP-2 and MMP-9 protein expression. In vivo tumorigenicity tests showed that 3a could inhibit the occurrence of TNBC by inhibiting BCSCs, proving 3a is a potential EGFR and CSC dual inhibitor for TNBC treatment.

ABCG2 requires a single aromatic amino acid to "clamp" substrates and inhibitors into the binding pocket.

ATP-binding cassette sub-family G member 2 (ABCG2) is a homodimeric ATP-binding cassette (ABC) transporter that not only has a key role in helping cancer cells to evade the cytotoxic effects of chemotherapy, but also in protecting organisms from multiple xeno- and endobiotics. Structural studies indicate that substrate and inhibitor (ligands) binding to ABCG2 can be differentiated quantitatively by the number of amino acid contacts, with inhibitors displaying more contacts. Although binding is the obligate initial step in the transport cycle, there is no empirical evidence for one amino acid being primarily responsible for ligand binding. By mutagenesis and biochemical studies, we demonstrated that the phylogenetically conserved amino acid residue, F439, was critical for both transport and the binding of multiple substrates and inhibitors. Structural modeling implied that the π-π interactions from each F439 monomer mediated the binding of a surprisingly diverse array of structurally unrelated substrates and inhibitors and that this symmetrical π-π interaction "clamps" the ligand into the binding pocket. Key molecular features of diverse ABCG2 ligands using the π-π clamp along with structural studies created a pharmacophore model. These novel findings have important therapeutic implications because key properties of ligands interacting with ABCG2 have been disovered. Furthermore, mechanistic insights have been revealed by demonstrating that for ABCG2 a single amino acid is essential for engaging and initiating transport of multiple drugs and xenobiotics.

Design, synthesis and biological evaluation of novel substituted purine isosters as EGFR kinase inhibitors, with promising pharmacokinetic profile and in vivo efficacy.

Novel substituted purine isosters, were designed and synthesized as potential inhibitors of the Epidermal Growth Factor Receptor (EGFR). The compounds were rationally designed through bioisosteric replacement of the central quinazoline core of lapatinib, an approved drug that inhibits both EGFR and HER2, another important member of this family of receptors. The new target molecules were evaluated as inhibitors of receptor phosphorylation at the cellular level, for their direct inhibitory action on the intracellular receptor kinase domain and for their cytotoxicity against the non-small cell lung cancer cell line A549 and breast cancer HCC1954, cell lines which are associated with overexpression of EGFR and HER2, respectively. The most potent derivatives were further studied for their cellular uptake levels and in vivo pharmacokinetic properties. One compound (23) displayed a noteworthy pharmacokinetic profile, and higher intracellular accumulation in comparison to lapatinib in the A549 cells, possibly due to its higher lipophilicity. This lead compound (23) was assessed for its efficacy in an EGFR positive xenograft model, where it successfully inhibited tumor growth, with a similar efficacy with that of lapatinib and with minimal phenotypic toxicity.

Improvement of Aqueous Solubility of Lapatinib-Derived Analogues: Identification of a Quinolinimine Lead for Human African Trypanosomiasis Drug Development.

Lapatinib, an approved epidermal growth factor receptor inhibitor, was explored as a starting point for the synthesis of new hits against Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). Previous work culminated in 1 (NEU-1953), which was part of a series typically associated with poor aqueous solubility. In this report, we present various medicinal chemistry strategies that were used to increase the aqueous solubility and improve the physicochemical profile without sacrificing antitrypanosomal potency. To rank trypanocidal hits, a new assay (summarized in a cytocidal effective concentration (CEC50)) was established, as part of the lead selection process. Increasing the sp3 carbon content of 1 resulted in 10e (0.19 µM EC50 against T. brucei and 990 µM aqueous solubility). Further chemical exploration of 10e yielded 22a, a trypanocidal quinolinimine (EC50: 0.013 µM; aqueous solubility: 880 µM; and CEC50: 0.18 µM). Compound 22a reduced parasitemia 109 fold in trypanosome-infected mice; it is an advanced lead for HAT drug development.