Abstract
The new molecular entity quinoxalinhydrazide derivative NVX-412 was identified as a promising drug candidate for the treatment of various cancer types due to its strong cytotoxic activity and relative specificity. Here, we provide first data about the mechanisms of action of NVX-412. We show that NVX-412 exerts its anti-neoplastic activity in a p53-independent manner and induces S-phase arrest and DNA damage as assessed by γH2AX staining. We suggest a bi-modal (dose-dependent) mode of action of NVX-412, being primarily cytostatic at lower and predominantly cytotoxic at higher concentrations. Based on the broad and consistent anti-neoplastic activity observed, NVX-412 holds promise as an effective drug candidate for the treatment of various cancer types, especially for hematological malignancies with highly unmet medical need.
Highlights
Cancer is one of the leading causes of death worldwide
Three different dose response parameters are calculated: growth inhibition of 50% (GI50), which is the drug concentration resulting in a 50% reduction in the net protein increase, the drug concentration resulting in total growth inhibition (TGI) and the LC50, indicating a net loss of cells following treatment [5]
NVX-412 Exerts Strong Anti-neoplastic Activity To obtain an independent overview of the range of activity of NVX-412 (Figure 1) against a panel of well-described cancer cell lines, the drug candidate was included in an anti-cancer activity screen conducted by the National Cancer Institute (NCI) against 59 different human tumor cell lines originating from various cancer types
Summary
Cancer is one of the leading causes of death worldwide. According to the World Health Organization cancer accounts for approximately 13% of all deaths worldwide [1]. Pyrazine-2-carboxylic acid N’- (7-fluoro-pyrrolo[1,2-a]quinoxalin-4-yl)-hydrazide-oxalic acid co-crystal, referred to as NVX412 (Figure 1), is a promising drug candidate for the treatment of a number of cancer types. This new molecular entity drug candidate fulfills the criteria of Lipinskis rule of five, which gives a first hint on drug-like properties and on whether a putative drug candidate may be suitable as a medicinal product [2]. NVX-1449s discovery and chemical structure was described by Grande and colleagues [3] It belongs to the chemical class of quinoxalinhydrazides and was developed via rational drug design [3]. NVX-412 confirms this notion by showing increased cytotoxic activity compared to the parental compound NVX-144 in HT-29 and HCT116 colon carcinoma cell lines with an IC50 that is 3 to 4-fold lower [3]
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