Recent Advances in the Discovery of CK2 Inhibitors.

CK2 is a vital enzyme that phosphorylates a large number of substrates and thereby controls many processes in the body. Its upregulation was reported in many cancer types. Inhibitors of CK2 might have anticancer activity, and two compounds are currently under clinical trials. However, both compounds are ATP-competitive inhibitors that may have off-target side effects. The development of allosteric and dual inhibitors can overcome this drawback. These inhibitors showed higher selectivity and specificity for the CK2 enzyme compared to the ATP-competitive inhibitors. The present review summarizes the efforts exerted in the last five years in the design of CK2 inhibitors.

Design and synthesis of certain 7-Aryl-2-Methyl-3-Substituted Pyrazolo{1,5-a}Pyrimidines as multikinase inhibitors.

Four new series 7a-e, 8a-e, 9a-e, and 10a-e of 7-aryl-3-substituted pyrazolo[1,5-a]pyrimidines were synthesized and tested for their RTK and STK inhibitory activity. Compound 7d demonstrated potent enzymatic inhibitory activity against TrkA and ALK2 with IC50 0.087and 0.105 µM, respectively, and potent antiproliferative activity against KM12 and EKVX cell lines with IC50 0.82 and 4.13 µM, respectively. Compound 10e showed good enzyme inhibitory activity against TrkA, ALK2, c-KIT, EGFR, PIM1, CK2α, CHK1, and CDK2 in submicromolar values. Additionally 10e revealed antiproliferative activity against MCF7, HCT116 and EKVX with IC50 3.36, 1.40 and 3.49 µM, respectively; with good safety profile. Moreover, 10e showed cell cycle arrest at the G1/S phase and G1 phase in MCF7 and HCT116 cells with good apoptotic effect. Molecular docking studies were fulfilled for compound 10e and illustrated good interaction with the hot spots of the active site of the tested enzymes.

Recent advances in the discovery of tropomyosin receptor kinases TRKs inhibitors: A mini review.

The tropomyosin receptor tyrosine kinases (TRKs) control the cell proliferation mainly in the nervous system and are encoded by NTRK genes. Fusion and mutation of NTRK genes were detected in various types of cancers. Many small molecules TRK inhibitors have been discovered during the last two decades and some of them have entered clinical trials. Moreover, two of these inhibitors; larotrectinib and entrectinib; were approved by FDA for the treatment of TRK-fusion positive solid tumors. However, mutation of TRK enzymes resulted in resistance to both drugs. Therefore, next generation TRK inhibitors were discovered to overcome the acquired drug resistance. Additionally, the off-target and on-target adverse effects on the brain initiated the need for selective TRK subtype inhibitors. Indeed, some molecules were recently reported as selective TRKA or TRKC inhibitors with minimal CNS side effects. The current review highlighted the efforts done during the last three years in the design and discovery of novel TRK inhibitors.