PQR620 is recognized as an orally bioavailable, brain-penetrant inhibitor with selectivity for mTORC1/2. It is a potent mTOR inhibitor, showing over 1000-fold selectivity against PI3Kα in binding assays. In A2058 melanoma cells, PQR620 inhibits phosphorylation of protein kinase B (pSer473) and ribosomal protein S6 (pSer235/236) with IC50 values of 0.2 μM and 0.1 μM, respectively. It also displays remarkable selectivity across a broad spectrum of kinases, unrelated receptor enzymes, and ion channels. PQR620's efficacy in halting cancer cell proliferation is demonstrated in an NTRC 44 cancer cell line panel[1]. When tested on 44 lymphoma cell lines, PQR620 has a median IC50 of 250 nM, showing greater activity in B cell tumors compared to T cell tumors (median IC50s: 250 nM vs 450 nM). After 72 hours, PQR620's anti-tumor activity is primarily cytostatic, with apoptosis observed in only 6 out of 44 cell lines (13%). Sensitivity to PQR620 and apoptosis induction are consistent between DLBCL and MCL, unaffected by the DLBCL cell of origin, TP53 status, or the presence of MYC or BCL2 translocations[2].
PQR620 动物研究
Animal study
The physicochemical properties of PQR620 confer good oral bioavailability and excellent brain penetration[1]. Its efficacy as a single agent has been evaluated in vivo in two DLBCL models: GCB-DLBCL SU-DHL-6 and ABC-DLBCL RIVA. Treatment with PQR620 (100 mg/kg daily, Qd×7/w) starting with tumors sized 100-150 mm3 is conducted for 14 days (SU-DHL-6) or 21 days (RIVA). In both models, PQR620 achieves a two-fold reduction in tumor volume compared to controls, with significant differences observed in SU-DHL-6 (D7, D9, D11, D14) and RIVA (D14, D16, D19, D21)[2].
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