PT2399 is a potent and selective HIF-2α antagonist that directly binds to the HIF-2α PAS B domain with an IC50 value of 6 nM. PT2399 has shown potent antitumour activity in vivo[1][2][3].PT2399 directly binds to the HIF-2α PAS B domain and impairs the ability of HIF-2α to bind to the aromatic hydrocarbon receptor nuclear transporter (ARNT)[2].At a concentration of 20 μM, PT2399 inhibited the proliferation of HIF-2α -/- 786-O cells and other cancer cell lines in which HIF-2α was undetectable, suggesting that PT2399 leads to off-target toxicity. PT2399 inhibited a variety of HIF-targeted genes in 786-O VHL-/- ccRCC cells, but not HIF-1α-specific target genes such as BNIP3[2].
PT2399 细胞实验
Cell Line
Concentration
Treated Time
Description
References
UMRC2
2 µM
2 to 5 weeks
Evaluate the effect of PT2399 on the growth of UMRC2 cells in soft agar, results showed PT2399 did not significantly suppress the growth of UMRC2 cells.
Proc Natl Acad Sci U S A. 2022 Apr 5;119(14):e2120403119
CAKI2
2 µM
2 to 5 weeks
Evaluate the effect of PT2399 on the growth of CAKI2 cells in soft agar, results showed PT2399 did not significantly suppress the growth of CAKI2 cells.
Proc Natl Acad Sci U S A. 2022 Apr 5;119(14):e2120403119
769-P
2 µM
2 to 5 weeks
Evaluate the effect of PT2399 on the growth of 769-P cells in soft agar, results showed PT2399 did not significantly suppress the growth of 769-P cells.
Proc Natl Acad Sci U S A. 2022 Apr 5;119(14):e2120403119
OSRC2
2 µM
2 to 5 weeks
Evaluate the effect of PT2399 on the growth of OSRC2 cells in soft agar, results showed PT2399 suppressed the growth of OSRC2 cells.
Proc Natl Acad Sci U S A. 2022 Apr 5;119(14):e2120403119
786-O
2 µM
2 to 5 weeks
Evaluate the effect of PT2399 on the growth of 786-O cells in soft agar, results showed PT2399 suppressed the growth of 786-O cells.
Proc Natl Acad Sci U S A. 2022 Apr 5;119(14):e2120403119
C4-2 cells
50 µM
24 hours
PT2399 significantly decreased HSD3B1 expression in HR cells and inhibited nuclear localization of HIF2α and its binding to ARNT.
Cancer Res. 2022 Jul 5;82(13):2417-2430
LNCaP cells
50 µM
24 hours
PT2399 significantly decreased HSD3B1 expression in HR cells and inhibited nuclear localization of HIF2α and its binding to ARNT.
Cancer Res. 2022 Jul 5;82(13):2417-2430
769-P cells
2 µM
48 hours
PT2399 failed to down-regulate cyclin D1 abundance in 769-P cells.
Sci Signal. 2019 Oct 1;12(601):eaay0482
UMRC-2 cells
2 µM
48 hours
PT2399 failed to down-regulate cyclin D1 abundance in UMRC-2 cells.
Sci Signal. 2019 Oct 1;12(601):eaay0482
A498 cells
2 µM
48 hours
PT2399 had variable effects on basal cyclin D1 mRNA and protein abundance in the A498 cells.
Sci Signal. 2019 Oct 1;12(601):eaay0482
786-O cells
2 µM
48 hours
PT2399 monotherapy did not cause a statistically significant increase in the VHL-Tdtomato:EV-GFP ratio, consistent with earlier studies showing that 786-O cells tolerate the loss of HIF-2 α in short-term cultures under high serum conditions.
Sci Signal. 2019 Oct 1;12(601):eaay0482
PT2399 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Renal cell carcinoma tumorgraft model
Oral gavage
100 mg/kg
Every 12 hours for approximately 28 days
To evaluate the antitumor effects of PT2399 in a renal cell carcinoma tumorgraft model. Results showed PT2399 suppressed tumorigenesis in 56% of the lines and was more active than sunitinib.
Nature. 2016 Nov 3;539(7627):112-117
Nude mice
786-O cell orthotopic xenografts
Oral gavage
20 mg/kg
Daily for 28 days
PT2399 monotherapy, as expected, suppressed 786-O cell tumor growth, with a trend toward greater suppression with the combination with palbociclib.
Sci Signal. 2019 Oct 1;12(601):eaay0482
Mice
Adenomyosis mouse model
Oral gavage
30 mg/kg
Twice daily for 2 days
Inhibited HIF-2α expression and increased Hoxa10 and Hoxa11 expression
Reprod Biol Endocrinol. 2021 Jan 8;19(1):7
Mice
Epas1S305M/S305M knock-in mice
Oral gavage
30 mg/kg
Twice daily for 8 weeks
PT2399 suppressed HIF-2α target gene expression in wild-type mice, ameliorated high-fat diet-induced obesity and metabolic dysfunction, but had no effect in mutant mice.
Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):13240-13245
Female Ncr nude mice
786-O-Fluc cell orthotopic xenograft model
Oral gavage
30 mg/kg
Once daily for 28 days
Evaluate the effect of PT2399 on the growth of 786-O-Fluc cell xenografts, results showed PT2399 significantly inhibited tumor growth and reduced Cyclin D1 and Ki67 expression.
Proc Natl Acad Sci U S A. 2022 Apr 5;119(14):e2120403119
Mice (C57Bl/6J background)
Wild-type mice and HIF-2α conditional knockout mice
Oral gavage
50 mg/kg
Twice daily for 5 consecutive days followed by a 2-day washout period, total 14 days
PT2399 treatment ameliorated radiation-induced bone loss but resulted in reduced red blood cell (RBC) counts and hemoglobin (HGB) amounts, indicating an anemic side effect.
Sci Transl Med. 2023 Nov 29;15(724):eabo5217
C57BL/6 mice
Subcutaneous and orthotopic pancreatic cancer models with KPC cells
Oral gavage
50 mg/kg
5 days per week, twice daily, for 2-3 weeks
To evaluate the therapeutic effect of PT2399 combined with immune checkpoint blockade on pancreatic cancer. Results showed that PT2399 combined with αCTLA4 significantly slowed tumor growth and improved survival.
Gastroenterology. 2022 Jun;162(7):2018-2031
Mice
Vhl/Trp53/Rb1 mutant mouse model
Oral gavage
50 mg/kg
Twice daily for 14 days
Evaluating the therapeutic effects of PT2399 in a HIF-2α inhibitor-resistant mouse ccRCC model, showing no significant effect on tumor growth
Cancers (Basel). 2021 Sep 25;13(19):4801
Mice
786-O and OSRC2 orthotopic xenografts
Oral gavage
30 mg/kg
Daily for 28 days
Assess the suppression of tumor growth by PT2399
Proc Natl Acad Sci U S A. 2022 Apr 5;119(14):e2120403119
PT2399 动物研究
Animal study
Administered by oral gavage at a dose of 100 mg/kg every 12 hours, PT2399 inhibits the growth of multiple SU 11248-resistant tumours in RCC mice[1].
搜索
