Design, synthesis, and biological evaluation of novel substituted thiourea derivatives as potential anticancer agents for NSCLC by blocking K-Ras protein-effectors interactions

Abstract

Mutation of the proto-oncogene K-Ras is one of the most common molecular mechanisms in non-small cell lung cancer. Many drugs for treating lung cancer have been developed, however, due to clinical observed K-Ras mutations, corresponding chemotherapy and targeted therapy for such mutation are not efficient enough. In this study, on the basis of the crystal structure of K-Ras, 21 analogues (TKR01-TKR21) containing urea or thiourea were rationally designed, which can effectively inhibit the lung cancer cell A549 growth. The designing of these compounds was based on the structure of K-Ras protein, and the related groups were replaced by bioisosteres to improve the affinity and selectivity. Biological testing revealed that compound TKR15 could significantly inhibit the proliferation of A549 cell with IC 50 of 0.21 mM. Docking analysis showed that the TKR15 can effectively bind to the hydrophobic cavity and form a hydrogen bond with the Glu37. In addition, through flow apoptosis assay and immunofluorescence staining assay, it confirmed that this compound can inhibit A549 cell proliferation with the mechanism of blocking K-Ras G12V protein and effector proteins interactions through the apoptotic pathway. In conclusion, our studies in finding novel potent compound (TKR15) with confirmed mechanism showed great potential for further optimisation and other medicinal chemistry relevant studies.

The RASSF1A Tumor Suppressor Binds the RasGAP DAB2IP and Modulates RAS Activation in Lung Cancer

“…Recent work has raised the distinct possibility that the development of targeted inhibitors of RAS as therapeutic agents may be possible [ 11 , 50 , 51 , 52 ] These studies suggest that tumors without ras mutations, but with dual inactivation of RASSF1A and DAB2IP, may be sensitive to such agents.…”

Proapoptotic effects of halogenated bis‐phenylthiourea derivatives in cancer cells

“…[32][33][34]40] The choice of the size of amine rings (R 1 )-mainly phenyl, but also bulky carbazolyl-was dictated by the high probability of finding potent derivatives among them. [30,31,35,40,44] Therefore, the studies reported herein focused on various halogenated derivatives bearing aromatic amine nuclei of different size and substituents. The series was divided into subseries to highlight the differences in the structure of terminal amines, namely diarylthioureas: 4-bromo-2,6dichlorophenyl (1a), 4-chloro-3-nitrophenyl (3a, 3b), 3,3′dimethoxy-[1,1′-biphenyl (4a) and 2-cyanophenyl (5a-5j) and heteroaromatic 9-ethyl-9H-carbazol-3-yl (2a, 2b) derivatives.…”

“…[11] Substituted thiourea compounds have also been described in lung cancer cells as blockers of Ras kinase proteins of enzymes that are regulators of cell proliferation, differentiation, and survival. [31] Antiangiogenic properties of ureas/ thioureas were demonstrated by selective inhibition of tyrosine kinases in hepatocellular carcinoma, [15] lung cancer, [32] or vascular endothelial cells. [33] Anticancer agents can also act as inhibitors of other enzymes of different classes, such as hydrolases, oxidoreductases, or lyases, overexpressed in human tumors.…”

New Potential Agents for Malignant Melanoma Treatment—Most Recent Studies 2020–2022

“…As a result, modifications to the structure of ibrutinib are of great interest to scientists looking for anticancer drugs [ 68 ]. Based on the literature data, the thiourea moiety was introduced, which ensures selectivity, effectiveness, and favorable physicochemical parameters [ 69 , 70 , 71 , 72 , 73 ]. Compound (32) exhibited the highest activity against melanoma cell line B16 with an IC 50 = 6.07 ± 1.06 µM [ 74 ].…”