An Orally Bioavailable, Indole-3-glyoxylamide Based Series of Tubulin Polymerization Inhibitors Showing Tumor Growth Inhibition in a Mouse Xenograft Model of Head and Neck Cancer

Abstract

A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, although none has yet been successfully developed clinically. We report here a new series of related compounds, modified according to a strategy of reducing aromatic ring count and introducing a greater degree of saturation, which retain potent tubulin polymerization activity but with a distinct SAR from previously documented libraries. A subset of active compounds from the reported series is shown to interact with tubulin at the colchicine binding site, disrupt the cellular microtubule network, and exert a cytotoxic effect against multiple cancer cell lines. Two compounds demonstrated significant tumor growth inhibition in a mouse xenograft model of head and neck cancer, a type of the disease which often proves resistant to chemotherapy, supporting further development of the current series as potential new therapeutics.

The IL‐1/IL‐1R axis induces greater fibroblast‐derived chemokine release in human papillomavirus‐negative compared to positive oropharyngeal cancer

“…For IL‐1R blocking experiments, 6 × 10 5 NTF were incubated with 10 μg/mL anakinra or placebo control (Amgen, Thousand Oaks, CA) for 2 h before stimulation with conditioned medium from SCC89 OPC cells or medium containing 5 ng/mL recombinant IL‐1β as a positive control for 4 h. Levels of anakinra or placebo were maintained throughout the experiment. A cytotoxicity assay using the tetrazolium dye MTT was performed on anakinra treated NTF as previously described …”

“…A cytotoxicity assay using the tetrazolium dye MTT was performed on anakinra treated NTF as previously described. 25 siRNA treatment of NTF siRNA for IL-1R1 was performed according to the manufacturer's instructions (FlexiTube, Qiagen). Briefly, 3 × 10 5 NTF seeded in 6-well plates were incubated with transfection complex containing 300 nM siRNA (IL-1R1, oligonucleotide SI00017598) and Hi-PerFect transfection reagent (both Qiagen) in serum-free medium.…”

Learning Medicinal Chemistry Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Rules from Cross-Company Matched Molecular Pairs Analysis (MMPA)

“…Within the organizations collaborating in this work and in those who have been able to exploit the data in trial form in universities and not for profit organizations, the knowledge has contributed to solving a number of drug hunting project problems leading to several publications . [40][41][42] We have also shown examples of transformations that run counter to established wisdom. These may be useful tools to extricate a drug hunting team from a tight optimization corner and more generally to provide opportunities to enhance our understanding of the general SAR of the system being studied.…”

2-[2-Methyl-5-phenyl-1-(3,4,5-trimethoxyphenyl)-1H-pyrrol-3-yl]-2-oxo-N-(pyridin-4-yl) acetamide

“…Unlike many anti-mitotic agents, it does not exert peripheral neuropathy; this benefit distinguishes indibulin from other similar acting compounds [14]. Significant efforts have been made to find new anti-tubulin derivatives, inspired by the structure of indibulin [15][16][17] (Figure 2). Indibulin ( Figure 2) is a new generation of anticancer compound with anti-mitotic properties.…”