Oxadiazoles and thiadiazoles as TGF-beta inhibitors

Abstract

The present disclosure is concerned with oxadiazole and thiadiazole analogs that are capable of inhibiting TGF-beta and methods of treating cancers such as, for example, multiple myeloma and a hematologic malignancy, and methods of treating fibrotic conditions using these compounds. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended tobe limiting of the present invention.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 577,608, filed October 26, 2017, the contents of which are hereby incorporated by reference in their entirety. [0003] Statement Regarding Federally Funded Research [0004] This invention was made with government support under Grant No. 1R01 CA175012 awarded by the National Institutes of Health. The government has certain rights in this invention. Background technique [0005] TGF-β is a central regulator of chronic liver disease by inducing fibrogenesis responses (Weskirchen and Tacke (2016) Dig Dis 34:410-422; Katz et al. (2016) Cancer letters 379:166-172; Yoshida et al. (2014) ) Int J Oncol 45: 1363-1371; Fabregat et al. (2016) The FEBS journal 283: 2219-2232; Xu et al. (2016) J Histochem Cytochem 64: 157-167). Although infiltrating macrophages are a source of TGF-β, hepatic stellate cells are an important source of TGF-β in liver fibrosis...

AI Technical Summary

Problems solved by technology

Systemic administration of LSKL-blocking peptides did not reduce Smad signaling or reduce skin wound healing in diabetic mice, however these studies did not address the effect of direct application of LSKL to wounds, and it is unclear Are local skin levels of LSKL sufficient to alter local TGF-β activation (Lu et al. (2011) Am J Pathol 178:2573-2586)

[0014] Although peptides containing the amino acid sequence LSKL capable of stimulating TGF-β activity are known, these peptides are generally expensive and difficult to synthesize

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