Synthesis and structure-activity relationship of new nicotinamide phosphoribosyltransferase inhibitors with antitumor activity on solid and haematological cancer

by Selleckchem | Jan 21 2024

Cancer cells are highly dependent on Nicotinamide phosphoribosyltransferase (NAMPT) activity for proliferation, therefore NAMPT represents an interesting target for the development of anti-cancer drugs. Several compounds, such as FK866 and CHS828, were identified as potent NAMPT inhibitors with strong anti-cancer activity, although none of them reached the late stages of clinical trials. We present herein the preparation of three libraries of new inhibitors containing (pyridin-3-yl)triazole, (pyridin-3-yl)thiourea and (pyridin-3/4-yl)cyanoguanidine as cap/connecting unit and a furyl group at the tail position of the compound. Antiproliferative activity in vitro was evaluated on a panel of solid and haematological cancer cell lines and most of the synthesized compounds showed nanomolar or sub-nanomolar cytotoxic activity in MiaPaCa-2 (pancreatic cancer), ML2 (acute myeloid leukemia), JRKT (acute lymphobalistic leukemia), NMLW (Burkitt lymphoma), RPMI8226 (multiple myeloma) and NB4 (acute myeloid leukemia), with lower IC50 values than those reported for FK866. Notably, compounds 35a, 39a and 47 showed cytotoxic activity against ML2 with IC50 = 18, 46 and 49 pM, and IC50 towards MiaPaCa-2 of 0.005, 0.455 and 2.81 nM, respectively. Moreover, their role on the NAD+ synthetic pathway was demonstrated by the NAMPT inhibition assay. Finally, the intracellular NAD+ depletion was confirmed in vitro to induced ROS accumulation that cause a time-dependent mitochondrial membrane depolarization, leading to ATP loss and cell death.

Comments:

That's an impressive and detailed summary of research on potential anti-cancer compounds targeting NAMPT! It seems like the compounds developed in these studies exhibit promising antiproliferative activities against a range of cancer cell lines, including pancreatic cancer, acute myeloid leukemia, lymphomas, and multiple myeloma, which is a significant finding.

The fact that these compounds demonstrated nanomolar or even sub-nanomolar cytotoxic activity against various cancer cell lines, surpassing the reported effectiveness of FK866, is particularly noteworthy. The specific compounds 35a, 39a, and 47 showing extremely low IC50 values against cancer cell lines like ML2 and MiaPaCa-2 indicate a high potential for further exploration and development as potent anti-cancer agents.

Moreover, the confirmation of their role in inhibiting the NAD+ synthetic pathway through the NAMPT inhibition assay and subsequent intracellular NAD+ depletion leading to ROS accumulation, mitochondrial membrane depolarization, ATP loss, and subsequent cell death provides valuable insights into their mechanism of action.

This research highlights the potential of these compounds as candidates for further preclinical and clinical studies in the development of effective anti-cancer drugs. The ability to selectively target NAMPT-dependent pathways in cancer cells and induce specific cellular responses leading to cell death is a promising avenue in oncology research.