SG-2000

Aberrant elevated Src activity is related to lung cancer growth and metastasis. Therefore, the development of potent small molecule inhibitors to target Src kinase is a potential therapeutic strategy for lung cancer. This study aimed to develop a computational model for the in silico screening of Src inhibitors and then assess the suppressive effect of candidate compounds on cellular functions. A 3D-quantitative structure-activity relationship (QSAR) pharmacophore model consisting of two hydrogen bond acceptors and two hydrophobic regions was constructed by using 28 structurally diverse compounds with IC₅₀ values spanning four orders of magnitude. A National Cancer Institute (NCI) compound dataset was employed for virtual screening by applying the pharmacophore model and molecular docking. Candidate compounds were chosen from the top 20% of scored hits. Among these compounds, the suppressive effects of 30 compounds available in the NCI on Src phosphorylation were validated by using an enzyme-linked immunosorbent assay. Among these compounds, SJG-136, a pyrrolobenzodiazepine dimer, showed a significant inhibitory effect against Src activity in a dose-dependent manner. Further investigations showed that SJG-136 can inhibit lung cancer cell proliferation, clonogenicity, invasion and migration in vitro and tumour growth in vivo. Furthermore, SJG-136 also had an inhibitory effect on Src-related signaling pathways, including the FAK, paxillin, p130Cas, PI3K, AKT, and MEK pathways. In conclusion, we have established a pharmacophore-based virtual screening approach to identify novel Src inhibitors that can inhibit lung cancer cell growth and motility through suppressing Src-related pathways. These findings may contribute to the development of targeted drugs for lung cancer treatment, such as lead compounds.

The pyrrolo[2,1‐c][1,4]benzodiazepines (PBDs) are a family of sequence‐selective DNA minor‐groove binding agents that form a covalent aminal bond between their C11‐position and the C2‐NH2groups of guanine bases. The first example of a PBD monomer, the natural product anthramycin, was discovered in the 1960s, and the best known PBD dimer, SJG‐136 (also known as SG2000, NSC 694501 or BN2629), was synthesized in the 1990s and has recently completed Phase II clinical trials in patients with leukaemia and ovarian cancer. More recently, PBD dimer analogues are being attached to tumor‐targeting antibodies to create antibody–drug conjugates (ADCs), a number of which are now in clinical trials, with many others in pre‐clinical development. This Review maps the development from anthramycin to the first PBD dimers, and then to PBD‐containing ADCs, and explores both structure–activity relationships (SARs) and the biology of PBDs, and the strategies for their use as payloads for ADCs.