Recently, Arnst et al. characterized the novel tubulin polymerization inhibitor DJ95 as a small-molecule chemotherapeutic agent against multi-drug resistant (MDR) cancers. Anti-cancer therapeutics either stabilize or destabilize microtubules (MTs), leading to apoptosis and cell death in either scenario. A growing therapeutic problem is MDR with over-expression of ATP-binding cassette (ABC) transporters being a primary mechanism. Efficacy of DJ95 was evaluated in multiple separate cancer, MDR, and ABC transporter-overexpressing cell lines, as well as the National Cancer Institute 60 cell line panel. DJ95 inhibited cancer cell migration, disrupted the MT cytoskeleton, and significantly impaired mitotic spindle formation in cells undergoing mitosis. Additionally, the high-resolution crystal structure of DJ95 in complex with tubulin was determined, confirming its direct binding to the colchicine site. Surface plasmon resonance (SPR) experiments calculated DJ95’s binding affinity for tubulin. In an in vivo mouse xenograft model, DJ95 inhibited tumor growth and disrupted tumor vasculature. Cytoskeleton’s 99% pure porcine brain tubulin (Cat. # T238P) was the substrate in the in vitro X-ray crystallography and SPR binding affinity studies. Collectively, the data will guide further development of this novel, potent anti-cancer compound (and related indolylimidazopyridines) and continued evaluation of its suitability for treating MDR cancers.
Products used in this citation:
Tubulin-RB3_SLD-TTL in complex with compound DJ95. TLL, tubulin tyrosine ligase. PDB ID: 6NNG.