Navarixin

Intracellular ligands of G protein-coupled receptors (GPCRs) are gaining significant interest in drug discovery. Here, we report the development of the fluorescent ligand Mz437 (4) targeting the CC chemokine receptor CCR7 at an intracellular allosteric site. We demonstrate its experimental power by applying 4 to identify two improved intracellular CCR7 antagonists, SLW131 (10) and SLW132 (21m), developed by converting two weakly active antagonists into single- or double-digit nanomolar ligands with minimal modifications. The thiadiazoledioxide 10 was derived from the CCR7 antagonist Cmp2105 by removing a methyl group from the benzamide moiety, while the squaramide 21m was obtained from the CXCR1/CXCR2 antagonist and clinical candidate navarixin by replacing the ethyl substituent by a tert-butyl group to engage a lipophilic subpocket. We show that 10 and 21m qualify to probe CCR7 biology in recombinant and primary immune cells and expect our novel probes to facilitate the design of next-generation intracellular CCR7 ligands.

3,4-Dihydroxycyclobut-3-ene-1,2-dione (squaric acid, SQ) is the most important representative of the oxocarbon acids family. Squaric acid derivatives can be promising pharmaceutical agents, due to their unique structural properties, from which novel drugs benefit: a planar aromatic ring, the ability to form hydrogen bonds, good reactivity and similarity with carboxylate, phosphate and amide groups. These properties make it suitable for three major applications in cancer treatment. Firstly, due to their excellent ion binding ability, the halogenated squaramides can be used as artificial ion transporters or mobile carriers to disrupt Na⁺/Cl^- gradients in cancer cells, thus hindering lysosomal function and inducing apoptosis. Another advantage of this class is their bioisosteric properties. Such molecules have been reported to be selective inhibitors of HDACs, FAK, SNM1A, MMP and kinases, involved in tumor growth and metastasis. Finally, the cyclobutenedione moiety proves to be a great linker in complex radiopharmaceuticals, used in theranostics. Its aromaticity and good reactivity make the generation and stability of these drugs easy and efficient. Multiple derivatives containing the squamide motif have been the subject of in-vitro investigations and have demonstrated anti-cancer activity in the nanomolar range against tumor cell lines, including colorectal adenocarcinoma, breast cancer, gastric carcinoma and cervical cancer. On the other hand, squaric acid derivative-Navarixin, has already been evaluated in Phase II clinical trials for its potential efficacy in the treatment of solid tumors. In this context this review is the first looking into the potential applications of squaric acid derivatives as anticancer therapies. It analyzes experimental studies presented in articles published between 2000 and 2024.