Avidin Ltd. synthesized several new imidazo-pyrazole carboxamides and constructed a more than 60‐membered library for structure–activity relationship (SAR) determination. The lead molecule DU385 exhibits sub-micromolar activity on human acute promyelocytic leukemia and human colon cancer cells with great selectivity.

Preclinical Results

Eight derivatives showed great cytotoxic activity against five leukemia cell lines: acute promyelocytic leukemia (HL-60); acute monocytic leukemia (THP-1); acute T-lymphoblastic leukemia (MOLT-4); biphenotypic B myelomonocytic leukemia (MV-4-11); and erythroleukemia (K-562) cells in vitro. Optimization through structure activity relationship resulted in lead compound DU385, which exhibited nanomolar activity in vitro on human acute promyelocytic leukemia and human colon cancer cell lines, but with much less toxicity on human primary fibroblasts and other measured cancer cell types.

Mechanisms of Action

Toxicogenomic screening showed that DU385 depressed early stress-related genes; elevated early endoplasmic reticulum stress-associated genes and chaperons; upregulated genes associated with differentiation, cell adhesion, cell survival and apoptosis. Moreover, differentiation and subsequent apoptosis of pre-matured myeloid leukemia cells or myeloid-derived suppressors are induced.

Szebeni et al. 2019

Applications

The lead imidazo-pyrazole carboxamide molecules were developed to possess impressive and selective anticancer activity, which have been tested in human and murine cells and in different types of cancers. These characteristics enable the molecules to fight acute myelogenous/myeloid leukemia and colon cancer.

Intellectual Property (IP) position

Our latest patent titled Imidazo-pyrazole carboxamide derivatives as anticancer agents and the synthesis is under national patenting process at the moment. The international patent application has been initiated on May 17, 2019.