Advances in the discovery of activin receptor-like kinase 5 (ALK5) inhibitors.

Activin receptor­like kinase-5 (ALK5) is an outstanding member of the transforming growth factor-ß (TGF-ß) family. (TGF-ß) signaling pathway integrates pleiotropic proteins that regulate various cellular processes such as growth, proliferation, and differentiation. Dysregulation within the signaling pathway can cause variety of diseases, such as fibrosis, cardiovascular disease, and especially cancer, rendering ALK5 a potential drug target. Hence, various small molecules have been designed and synthesized as potent ALK5 inhibitors. In this review, we shed light on the current ATP-competitive inhibitors of ALK5 through diverse heterocyclic based scaffolds that are in clinical or pre-clinical phases of development. Moreover, we focused on the binding interactions of the compounds to the ATP binding site and the structure-activity relationship (SAR) of each scaffold, revealing new scopes for designing novel candidates with enhanced selectivity and metabolic profiles.

Identification of novel furo[2,3-d]pyrimidine based chalcones as potent anti-breast cancer agents: synthesis, in vitro and in vivo biological evaluation.

Various substituted synthetic chalcones demonstrated potent anti-cancer activities. In the current study a series of novel furo[2,3-d]pyrimidine based chalcones were synthesized as potential anticancer agents. Among the different substituted derivatives, two of the halogen bearing chalcones, 5d and 5e, demonstrated potent anti-proliferative activity against an NCI 59 cell line, with mean GI50 values of 2.41 µM and 1.23 µM, respectively. Moreover, both compounds showed pronounced cytotoxic activity (5d; 1.20 ± 0.21, 5e; 1.90 ± 0.32) against the resistant MCF-7 cell line when compared to doxorubicin; 3.30 ± 0.18. Such outcomes provoked the initiation of an in vivo anticancer assessment study, where compound 5e revealed comparable results to doxorubicin.

Elaborating piperazinyl-furopyrimidine based scaffolds as phosphoinositol-3-kinase enzyme alpha (PI3Kα) inhibitors to combat pancreatic cancer.

Phosphoinositol-3-kinase enzyme (PI3K) plays a crucial role in driving oncogenic growth in various mammalian cells, particularly pancreatic cells. In the current study a series of novel furo[2,3-d]pyrimidine based-compounds were designed and synthesized as potential PI3K-α inhibitors. In accordance to the structure-activity relationship (SAR) studies of known PI3K-α inhibitors, different linkers including amide, urea and ether were attached to a piperazinyl furo[2,3-d]pyrimidine core. The synthesized compounds that revealed moderate PI3K-α inhibitory activity were tested for their anti-proliferative activities against pancreatic carcinoma on the PANC-1 cell line. Compounds 7b and 8a showed the highest anti-proliferative activity with IC50 values of 4.5 µM and 6 µM, respectively and relatively, the best in vitro PI3K inhibition ability within the newly synthesized compounds. Additionally, all the newly synthesized final compounds were tested on 60 human cancer cell lines. A docking study was carried out on the PI3K-α active site showing a comparable binding mode to that of FDA approved PI3K-α inhibitors. These newly discovered lipid kinase inhibitors could be considered as potential candidates for the development of new targeted anticancer agents.