Biological activity of a stable 6-aryl-2-benzoyl-pyridine colchicine-binding site inhibitor, 60c, in metastatic, triple-negative breast cancer.

BACKGROUND: Improving survival for patients diagnosed with metastatic disease and overcoming chemoresistance remain significant clinical challenges in treating breast cancer. Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by a lack of therapeutically targetable receptors (ER/PR/HER2). TNBC therapy includes a combination of cytotoxic chemotherapies, including microtubule-targeting agents (MTAs) like paclitaxel (taxane class) or eribulin (vinca class); however, there are currently no FDA-approved MTAs that bind to the colchicine-binding site. Approximately 70 % of patients who initially respond to paclitaxel will develop taxane resistance (TxR). We previously reported that an orally bioavailable colchicine-binding site inhibitor (CBSI), VERU-111, inhibits TNBC tumor growth and treats pre-established metastatic disease. To further improve the potency and metabolic stability of VERU-111, we created next-generation derivatives of its scaffold, including 60c. RESULTS: 60c shows improved in vitro potency compared to VERU-111 for taxane-sensitive and TxR TNBC models, and suppress TxR primary tumor growth without gross toxicity. 60c also suppressed the expansion of axillary lymph node metastases existing prior to treatment. Comparative analysis of excised organs for metastasis between 60c and VERU-111 suggested that 60c has unique anti-metastatic tropism. 60c completely suppressed metastases to the spleen and was more potent to reduce metastatic burden in the leg bones and kidney. In contrast, VERU-111 preferentially inhibited liver metastases and lung metastasis repression was similar. Together, these results position 60c as an additional promising CBSI for TNBC therapy, particularly for patients with TxR disease.

Study on forced degradation behaviour of dofetilide by LC-PDA and Q-TOF/MS/MS: Mechanistic explanations of hydrolytic, oxidative and photocatalytic rearrangement of degradation products.

A solution and solid state forced decomposition study was carried on dofetilide under diverse stress conditions of hydrolysis, oxidation, photolysis and thermal as per International Council for Harmonisation guidelines (ICH) Q1A(R2) to understand its degradation behaviour. A total of eight degradation products (DPs) were identified and separated on reversed phase kromasil 100 C8 column (4.6 mm x 250 mm x5 µm) using gradient elution with ammonium acetate (10 mM, pH 6.2) and acetonitrile as mobile phase. The detection wavelength was selected as 230 nm. The high performance liquid chromatography (HPLC) study found that the drug was susceptible to hydrolytic stress condition, but it was highly unstable to photolytic and oxidative conditions. The solid drug was stable in thermal and photolytic conditions. Initially comprehensive mass fragmentation pattern of the drug was accomplished with the LC/ESI/QTOF/MS/MS studies in positive ionization mode. The same was followed for all the eight degradation products to characterise their structure. The DP4 was N-oxide and the structure was confirmed by LC/APCI/QTOF/MS/MS in positive ionization mode. The complete mass fragmentation pattern of the drug and its DPs were established which in turn helped the characterisation of their structures. The mechanistic pathway for the formation of all the DPs was explained.