Computational approaches applied in drug discovery have advanced significantly over the past few decades. These techniques are commonly grouped under the term “computer-aided drug design” (CADD) and are now considered one of the key pillars of pharmaceutical discovery pipelines in both academic and industrial settings. In this work, we review Quantitative Structure–Activity Relationships (QSARs), one of the most used ligand-based drug design (LBDD) methods, with a focus on its application in the discovery and development of anti-breast cancer drugs. Critical steps in the QSAR methodology, essential for its correct application—but often overlooked, leading to insignificant or misleading models—are examined. Additionally, current anti-breast cancer treatment strategies were briefly overviewed, along with some targets for future treatments. The review covers QSAR studies from the past five years and includes a discussion of notable works that could serve as models for future applications of this interdisciplinary and complex method and that may help in feature drug design and development.

With the introduction of Navarixin in clinical trials, the role of squaric acid derivatives as bioisosteres gained popularity. Because of their distinctive electronic properties and hydrogen-bonding capacity, these compounds hold considerable promise for medicinal chemistry applications. In this study, a series of novel furan- and thiophene-containing squaric acid derivatives was synthesized via base-catalyzed nucleophilic substitution and characterized by spectroscopic techniques. The structures of three compounds were additionally confirmed by X-ray crystallography. Density functional theory calculations showed good agreement with the experimental vibrational spectra. In silico evaluation predicted favorable drug-like characteristics, including compliance with Lipinski’s rule of five and high gastrointestinal absorption. The cytotoxic activity of the synthesized compounds was assessed against HeLa, HT-29, HL-60, A-549, and MCF-7 cancer cell lines, as well as the non-cancerous CCL-1 cell line. Several derivatives displayed moderate to strong antiproliferative activity with selectivity toward malignant cells. Compound 3d exhibited the most pronounced improvement (five-fold) over Navarixin in HL-60 cells 5.81 µM, while compounds 3a and 3c demonstrated superior potency and selectivity in A-549 cells (10.33 µM and 9.65 µM). These findings identify squaric acid derivatives as promising candidates for further anticancer drug development and structure–activity relationship studies.