Reprofiling of pyrimidine-based DAPK1/CSF1R dual inhibitors: identification of 2,5-diamino-4-pyrimidinol derivatives as novel potential anticancer lead compounds

Abstract

Hybridization of reported weakly active antiproliferative hit 5-amino-4-pyrimidinol derivative with 2-anilino-4-phenoxypyrimidines suggests a series of 2,5-diamino-4-pyrimidinol derivatives as potential antiproliferative agents. Few compounds belonging to the proposed series were reported as CSF1R/DAPK1 inhibitors as anti-tauopathies. However, the correlation between CSF1R/DAPK1 signalling pathways and cancer progression provides motives to reprofile them against cancer therapy. The compounds were synthesised, characterized, and evaluated against M-NFS-60 cells and a kinase panel which bolstered predictions of their antiproliferative activity and suggested the involvement of diverse molecular targets. Compound 6e, the most potent in the series, showed prominent broad-spectrum antiproliferative activity inhibiting the growth of hematological, NSCLC, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers by 84.1, 52.79, 72.15, 66.34, 66.48, 51.55, 55.95, 61.85, and 60.87%, respectively. Additionally, it elicited an IC50 value of 1.97 µM against M-NFS-60 cells and good GIT absorption with Pe value of 19.0 ± 1.1 × 10−6 cm/s (PAMPA-GIT). Molecular docking study for 6e with CSF1R and DAPK1 was done to help to understand the binding mode with both kinases. Collectively, compound 6e could be a potential lead compound for further development of anticancer therapies.

Identification of SARS‐CoV‐2 Papain‐like Protease (PLpro) Inhibitors Using Combined Computational Approach**

“…[25] Computational drug repurposing was an essential step in successfully affording agents against other pathogenic diseases, [26] inflammation, [27] cancer. [28] The fundamental problem in a search for preventive and therapeutic options to respond to threats of a pandemic is a costly, time-consuming, and risky process of drug development.…”

Increased expression of UBE2T predicting poor survival of ovarian cancer: based on comprehensive analysis of UBE2s, clinical samples and the GEO database

“…Hence, the presence of B cells is a predictor of improved survival in patients with OC [66]. CSF1R is overexpressed in OC and the determination of its circulating levels proved useful for disease detection and the evaluation of therapeutic e cacy [67]. It has been reported that the cells of ovarian carcinoma produce large amounts of TGF-β1, which facilitates their escape from the immune system, and the clinical e cacy of immunotherapy based on TGF-β1-silenced tumor vaccines for OC has been investigated [68].…”

Synthetic and Naturally Occurring Heterocyclic Anticancer Compounds with Multiple Biological Targets

“…A demonstration of weak in vitro/in vivo activity by a hit compound is often exploited in the selection of an initial scaffold or starting material for the synthesis of improved bioactive compounds. Employing this approach, Farag et al synthesized seven derivatives of 5-amino-4-pyrimidinol of which compound 59 showed broad spectrum anti-cancer activity, with the indicated percentage inhibitions of the following cancers: hematological (84.1%), colon (72,15%), CNS (66.34%), melanoma (66.48%), ovarian (51.55%), renal (55.95%), prostate (61.85%), and breast (60.87%) [ 67 ]. ( N -(2-aminophenyl) benzamide acridine is another chemotype whose derivatives have been found to show improved suicidal action on tumor cells [ 68 ].…”