WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H205747
CAS#: 1007207-67-1 (free base)
Description: CH5132799, also known as PA-799, is a novel class I PI3K inhibitor, which exhibited a strong inhibitory activity especially against PI3Kα (IC(50)=0.014 μM). In human tumor cell lines with PI3K pathway activation, CH5132799 showed potent antiproliferative activity. CH5132799 is orally available and showed significant antitumor activity in PI3K pathway-activated human cancer xenograft models in mice. CH5132799 selectively inhibited class I PI3Ks and PI3Kα mutants in in vitro kinase assays. Tumors harboring PIK3CA mutations were significantly sensitive to CH5132799 in vitro and were remarkably regressed by CH5132799 in in vivo mouse xenograft models.
Hodoodo Cat#: H205747
Name: CH5132799
CAS#: 1007207-67-1 (free base)
Chemical Formula: C15H19N7O3S
Exact Mass: 377.13
Molecular Weight: 377.421
Elemental Analysis: C, 47.73; H, 5.07; N, 25.98; O, 12.72; S, 8.50
Related CAS #: 1007207-67-1 (free base) 2242053-82-1 (mesylate)
Synonym: CH5132799; CH-5132799; CH 5132799; PA-799; PA799; PA-799; Izorlisib
IUPAC/Chemical Name: 5-(7-(methylsulfonyl)-2-morpholino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-2-amine
InChi Key: JEGHXKRHKHPBJD-UHFFFAOYSA-N
InChi Code: InChI=1S/C15H19N7O3S/c1-26(23,24)22-3-2-11-12(10-8-17-14(16)18-9-10)19-15(20-13(11)22)21-4-6-25-7-5-21/h8-9H,2-7H2,1H3,(H2,16,17,18)
SMILES Code: NC1=NC=C(C2=C3C(N(S(=O)(C)=O)CC3)=NC(N4CCOCC4)=N2)C=N1
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not soluble in water.
Shelf Life: >5 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info: CH5132799 selectively inhibited class I PI3Ks and PI3Kα mutants in in vitro kinase assays. Tumors harboring PIK3CA mutations were significantly sensitive to CH5132799 in vitro and were remarkably regressed by CH5132799 in in vivo mouse xenograft models. In combination with trastuzumab, tumors disappeared in the trastuzumab-insensitive breast cancer model with the PIK3CA mutation. Moreover, CH5132799 did not reverse a negative feedback loop of PI3K/Akt/mTOR signaling and induced regression against tumors regrown after long-term mTORC1 inhibitor treatment. CONCLUSIONS: CH5132799 is a selective class I PI3K inhibitor with potent antitumor activity against tumors harboring the PIK3CA mutations. Prediction of CH5132799 response on the basis of PIK3CA mutations could enable patient stratification in clinical settings. (source: Clin Cancer Res. 2011 May 15;17(10):3272-81).
| Biological target: | CH5132799 is a selective class I PI3K inhibitor. CH5132799 inhibits class I PI3Ks, particularly PI3Kα, with an IC50 of 14 nM. |
| In vitro activity: | CH5132799 is a selective class I PI3K inhibitor with potent antitumor activity against tumors harboring the PIK3CA mutations. CH5132799 selectively inhibits class I PI3Ks and PI3Kα mutants in in vitro kinase assays. CH5132799 inhibits class I PI3Ks, particularly PI3Kα, with an IC50 of 14 nM. IC50 values against class II PI3Ks (C2α and C2β), a class III PI3K (Vps34), and a class IV PI3K (mTOR) are more than 100-fold higher than that against PI3Kα. Interestingly, slightly lower IC50 values are observed against PI3Kα with oncogenic mutations E542K, E545K, and H1047R than against wild-type (WT) PI3Kα. In an analysis of cocrystal structure with PI3Kγ (PBD ID: 3APC), CH5132799 is shown to interact with ATP-binding sites of the enzyme, suggesting an ATP competitive mode of inhibition. No significant inhibitory activities of CH5132799 are observed against a representative panel of 26 protein kinases, including RTKs, nonreceptor tyrosine kinases, and serine/threonine kinases. These data indicate that CH5132799 is a selective class I PI3K inhibitor, especially against PI3Kα and its mutants. CH5132799 shows superior antiproliferative activity across the 4 tumor types, with 75% (45/60) of lines having an IC50 below 1 μM and 38% (23/60) of lines having an IC50 below 0.3 μM. Reference: Clin Cancer Res. 2011 May 15;17(10):3272-81. http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=21558396 |
| In vivo activity: | Mice bearing BT-474 tumors (n=14) are orally administered 50 mg/kg of Everolimus on a daily basis for 31 days and then randomized. After randomization, the mice are orally administered 50 mg/kg of Everolimus (n=4) and 12.5 mg/kg (n=5), and 25 mg/kg (n=5) of CH5132799 on a daily basis for 7 days. C, the vehicle-, Everolimus, and CH5132799-treated (25 mg/kg) tumors are resected at 4 hours after terminal administration in B, lysed, and analyzed by Western blotting. CH5132799 administration leads to a remarkable regression in a dose-dependent manner of the tumors regrown after the long-term Everolimus treatment. The tumors are resected at the end of treatment and analyzed by Western blotting with respect to PI3K pathway inhibition. CH5132799 suppresses various effectors in the PI3K pathway, including Akt, FoxO1, S6K, S6, and 4E-BP1, whereas Everolimus inhibits only phosphorylation of S6K and S6, both downstream effectors of mTORC1. Reference: Clin Cancer Res. 2011 May 15;17(10):3272-81. http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=21558396 |
The following data is based on the product molecular weight 377.42 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | |
| In vitro protocol: | 1. Tanaka H, Yoshida M, Tanimura H, Fujii T, Sakata K, Tachibana Y, Ohwada J, Ebiike H, Kuramoto S, Morita K, Yoshimura Y, Yamazaki T, Ishii N, Kondoh O, Aoki Y. The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011 May 15;17(10):3272-81. doi: 10.1158/1078-0432.CCR-10-2882. Epub 2011 May 10. PMID: 21558396. |
| In vivo protocol: | 1. Tanaka H, Yoshida M, Tanimura H, Fujii T, Sakata K, Tachibana Y, Ohwada J, Ebiike H, Kuramoto S, Morita K, Yoshimura Y, Yamazaki T, Ishii N, Kondoh O, Aoki Y. The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011 May 15;17(10):3272-81. doi: 10.1158/1078-0432.CCR-10-2882. Epub 2011 May 10. PMID: 21558396. |
1: Correction: First-in-Human Study of CH5132799, an Oral Class I PI3K Inhibitor, Studying Toxicity, Pharmacokinetics, and Pharmacodynamics, in Patients with Metastatic Cancer. Clin Cancer Res. 2015 Feb 1;21(3):660. doi: 10.1158/1078-0432.CCR-14-3188. PubMed PMID: 25646183.
2: Blagden S, Omlin A, Josephs D, Stavraka C, Zivi A, Pinato DJ, Anthoney A, Decordova S, Swales K, Riisnaes R, Pope L, Noguchi K, Shiokawa R, Inatani M, Prince J, Jones K, Twelves C, Spicer J, Banerji U. First-in-human study of CH5132799, an oral class I PI3K inhibitor, studying toxicity, pharmacokinetics, and pharmacodynamics, in patients with metastatic cancer. Clin Cancer Res. 2014 Dec 1;20(23):5908-17. doi: 10.1158/1078-0432.CCR-14-1315. Epub 2014 Sep 17. Erratum in: Clin Cancer Res. 2015 Feb 1;21(3):660. Olmin, Aurelius [corrected to Omlin, Aurelius]. PubMed PMID: 25231405; PubMed Central PMCID: PMC4254850.
3: Tanaka H, Yoshida M, Tanimura H, Fujii T, Sakata K, Tachibana Y, Ohwada J, Ebiike H, Kuramoto S, Morita K, Yoshimura Y, Yamazaki T, Ishii N, Kondoh O, Aoki Y. The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011 May 15;17(10):3272-81. doi: 10.1158/1078-0432.CCR-10-2882. Epub 2011 May 10. PubMed PMID: 21558396.
4: Ohwada J, Ebiike H, Kawada H, Tsukazaki M, Nakamura M, Miyazaki T, Morikami K, Yoshinari K, Yoshida M, Kondoh O, Kuramoto S, Ogawa K, Aoki Y, Shimma N. Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799. Bioorg Med Chem Lett. 2011 Mar 15;21(6):1767-72. doi: 10.1016/j.bmcl.2011.01.065. Epub 2011 Jan 22. PubMed PMID: 21316229.
