Trifluoromethyl arylamides with antileukemia effect and intracellular inhibitory activity over serine/arginine-rich protein kinases (SRPKs)

Abstract

The serine/arginine-rich protein kinases (SRPKs) have frequently been found with altered activity in a number of cancers, suggesting they could serve as potential therapeutic targets in oncology. Here we describe the synthesis of a series of twenty-two trifluoromethyl arylamides based on the known SRPKs inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) and the evaluation of their antileukemia effects. Some derivatives presented superior cytotoxic effects against myeloid and lymphoid leukemia cell lines compared to SRPIN340. In particular, compounds 24, 30, and 36 presented IC values ranging between 6.0 and 35.7 μM. In addition, these three compounds were able to trigger apoptosis and autophagy, and to exhibit synergistic effects with the chemotherapeutic agent vincristine. Furthermore, compound 30 was more efficient than SRPIN340 in impairing the intracellular phosphorylation status of SR proteins as well as the expression of MAP2K1, MAP2K2, VEGF, and RON oncogenic isoforms. Therefore, novel compounds with increased intracellular effects against SRPK activity were obtained, contributing to medicinal chemistry efforts towards the development of new anticancer agents.

Cooperation of SRPK2, Numb and p53 in the malignant biology and chemosensitivity of colorectal cancer

“…SRPK2 promoted the cell proliferation of leukemia by regulating cyclin A1 (not cyclin A2) expression [11]. Consistent with the present study, SRPIN340, an inhibitor of SRPKs, showed antileukemic effects [32]. In hepatocellular carcinoma, SRPK2 silencing elevated Numb expression, which decreased cell migration and invasion by down-regulating Akt phosphorylation and c-Myc expression [33].…”

SRPK1 is a poor prognostic indicator and a novel potential therapeutic target for human colorectal cancer

“…SRPK1 inhibitors are being investigated as new anticancer agents. 26 , 27 Morooka et al 27 screened a large-scale chemical library to identify a new inhibitor of SRPK1, and the screened inhibitor SRPIN340 was found to prevent VEGF production more effectively in a mouse model of age-related macular degeneration, suggesting that silencing of SRPK1 could prevent neovascularization; this indicated that SRPK1 was a potential target for antiangiogenic drug development. The approach of the SRPK1 inhibitor “SPHINX” was also investigated to inhibit angiogenesis for prostate cancer treatment.…”

Serine-Arginine Protein Kinase 1 (SRPK1) as a Prognostic Factor and Potential Therapeutic Target in Cancer: Current Evidence and Future Perspectives

“…Of interest, SRPK1 pharmacologic inhibition with SPHINX31 did not impact normal hematopoiesis in the long term [65]. In other studies, SRPK1 downregulation suppressed proliferation and enhanced apoptosis in various leukemia types [66][67][68]. Siqueira et al also noted that the effect on apoptosis took place in a synergistic fashion with chemotherapy [67].…”

“…The SRPK1-induced PI3K/AKT pathway interacts with miR-1296 [45] ↑SRPK1 was found in hepatocellular cancer cell lines [46] ↑SRPK1 was found in hepatocellular cancer cell lines and promoted proliferation ↓SRPK1 suppressed proliferation in vitro and growth in vivo and in vitro SRPK1 interacts with the PI3K/AKT pathway [47] Esophagus ↑SRPK1 was found in esophageal cancer cell lines and promoted proliferation ↓SRPK1 suppressed proliferation, migration, and invasion and enhanced apoptosis in vitro also suppressed tumor growth in vivo SRPK1 interacts with the TGF-β pathways [48] Pancreas ↑SRPK1 was found in pancreatic cancer cell lines ↓SRPK1 suppressed proliferation and enhanced apoptosis and sensitivity to chemotherapy in vitro SRPK1 interacts with SR proteins and regulates apoptosis [22] SRPK1 interacts with the AKT and MAPK pathways [36] Blood (Leukemia) ↓SRPK1 suppressed proliferation in vitro and tumor growth in vivo, while it enhanced cell cycle arrest, apoptosis and prolonged the survival of animal models in MLL-rearranged AML; ↓SRPK1 switched BRD4 splicing, favoring the production of its long isoform SRPK1 modulates the alternative splicing of BRD4, MYB, and MED24 [65] ↑SRPK1 was found in various myeloid and lymphoid leukemia cell lines ↓SRPK1 was cytotoxic and enhanced apoptosis in vitro SRPK1 interacts with the SR proteins and modulates the expression and splicing of MAP2Ks, VEGF, and FAS [66] ↓SRPK1 suppressed proliferation while it enhanced autophagy and apoptosis in a synergistic fashion with chemotherapy in vitro SRPK1 interacts with SR proteins and modulates the expression of MAP2Ks and VEGF and the splicing of RON [67] ↓SRPK1 suppressed proliferation and enhanced apoptosis in vitro in CML SRPK1 interacts with the PARP-caspase-3 pathway [68] Kidney ↑SRPK1 was found in renal cancer cell lines ↓SRPK1 suppressed proliferation, migration, and invasion in vitro, also tumor growth in vivo SRPK1 interacts with PI3K/AKT pathway [50] Brain (Glioma) ↑SRPK1 was found in glioma cell lines ↓SRPK1 suppressed proliferation, migration, and invasion of glioma cells in vitro while it induced resistance to chemotherapy [51] ↓SRPK1 suppressed tumor growth and apoptosis in vivo, also angiogenesis in vitro and in vivo…”