Pim (provirus integration site for Moloney murine leukemia virus) family proteins are highly conserved serine/threonine kinases implicated in transcription, translation, cell cycle, survival, and drug resistance through the numerous targets. CX-6258 Hydrochloride is the hydrochloride form of CX-6258. CX-6258 is a selective and potent Pim inhibitor with IC50 values of 5nM, 25nM and 16nM for Pim-1, Pim-2 and Pim-3 (measured by SAR assay), respectively. Treatment with CX-6258 at concentration ranging in 0.1-10μM for 2h caused dose-dependent reduction of phosphorylation level of BAD, a substrate of Pim-1, and 4E-BP1-S65 and 4E-BP1-T37/46 in MV-4-11 cells. CX-6258 showed antiproliferative activity against a panel of cell lines derived from human solid tumors and hematological malignancies with IC50 values ranging in 0.02-3.7μM, most potent to acute leukemia cell lines. In vivo study showed that oral administration of CX-6258 at dose of 50 or 100mg/kg, once daily for 21 days reduced tumor growth in MV-4-11 xenograft models without obvious weight loss observed[1].
作用机制
CX-6258 can bind to the ATP binding pocket of Pim-1 enzyme.[1]
CX-6258 HCl 细胞实验
Cell Line
Concentration
Treated Time
Description
References
MM1S cells
5µM
12 h
Induced apoptosis, detected by PARP cleavage and Caspase 3 activation
Cancer Lett. 2019 Jan;440-441:1-10.
MM1R cells
5µM
12 h
Induced apoptosis, detected by PARP cleavage and Caspase 3 activation
Cancer Lett. 2019 Jan;440-441:1-10.
HeLa cells
40 nM
48 h
To study the effect of Pim1 knockdown on EV-A71 replication, results showed that Pim1 silencing significantly reduced viral RNA levels and viral titer.
iScience. 2019 Sep 27;19:715-727.
PC3 prostate adenocarcinoma cells
452 nM
Synergistic cell killing in combination with chemotherapeutics
A Potent, Selective, and Orally Efficacious pan-Pim Kinases Inhibitor. ACS Med Chem Lett.
CX-6258 HCl 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
MV-4-11 xenograft model
Oral
50 or 100 mg/kg
Once daily for 21 days
50 mg/kg dose produced 45% tumor growth inhibition (TGI) and a 100 mg/kg dose produced 75% TGI
A Potent, Selective, and Orally Efficacious pan-Pim Kinases Inhibitor. ACS Med Chem Lett.
NSG mice
Myeloma xenograft mouse model
Oral gavage
35 mg/kg
Daily for 3 weeks
Evaluated the anti-myeloma activity of CX-6258 in combination with lenalidomide, showing significant tumor growth inhibition
Cancer Lett. 2019 Jan;440-441:1-10.
Mice
Patient-derived xenograft models
Oral gavage
100 mg/kg
Four doses over 9 days
Evaluate the antitumor efficacy of CX-6258 in combination with CX-5461 against CRPC subtypes, showing significant reduction in tumor volume
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