Home > Compound List > Compound details
1007207-67-1 molecular structure
click picture or here to close

5-[7-methanesulfonyl-2-(morpholin-4-yl)-5H,6H,7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine

ChemBase ID: 73197
Molecular Formular: C15H19N7O3S
Molecular Mass: 377.42146
Monoisotopic Mass: 377.1270085
SMILES and InChIs

SMILES:
n1c(ncc(c1)c1c2c(nc(n1)N1CCOCC1)N(CC2)S(=O)(=O)C)N
Canonical SMILES:
Nc1ncc(cn1)c1nc(nc2c1CCN2S(=O)(=O)C)N1CCOCC1
InChI:
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)
InChIKey:
JEGHXKRHKHPBJD-UHFFFAOYSA-N

Cite this record

CBID:73197 http://www.chembase.cn/molecule-73197.html

Collapse All Expand All

NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
5-[7-methanesulfonyl-2-(morpholin-4-yl)-5H,6H,7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine
IUPAC Traditional name
5-[7-methanesulfonyl-2-(morpholin-4-yl)-5H,6H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine
Synonyms
CH5132799
CAS Number
1007207-67-1
PubChem SID
162038117
PubChem CID
49784945

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources
Data Source Data ID Price
Selleck Chemicals
S2699 external link Add to cart Please log in.
Data Source Data ID
PubChem 49784945 external link

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem
Acid pKa 16.183325  H Acceptors
H Donor LogD (pH = 5.5) -0.19831757 
LogD (pH = 7.4) -0.19143686  Log P -0.19134843 
Molar Refractivity 97.4493 cm3 Polarizability 37.481453 Å3
Polar Surface Area 127.43 Å2 Rotatable Bonds
Lipinski's Rule of Five true 

PROPERTIES

PROPERTIES

Safety Information Pharmacology Properties Product Information Bioassay(PubChem)
Storage Condition
-20°C expand Show data source
Target
PI3K expand Show data source
Salt Data
Free Base expand Show data source

DETAILS

DETAILS

Selleck Chemicals Selleck Chemicals
Selleck Chemicals - S2699 external link
Biological Activity
Description CH5132799 exhibits a strong inhibitory activity especially against PI3Kα with IC50 of 14 nM.
Targets PI3Kα PI3Kβ PI3Kδ PI3Kγ
IC50 0.014 μM 0.12 μM 0.50 μM 0.036 μM [1]
In Vitro CH5132799 selectively inhibits class I PI3Ks, PI3Kα (IC50 = 0.014 μM ), PI3Kβ (IC50 = 0.12 μM ), PI3Kδ (IC50 = 0.50 μM ), PI3Kγ (IC50 = 0.036 μM ), but shows less inhibition of class II PI3Ks, class III PI3k and mTOR and also no inhibitory activity (IC50 > 10 μM) against 26 protein kinases. CH5132799 exhibits more inhibitory activities against PI3Kα with oncogenic mutations E542K (IC50 = 6.7 nM), E545K (IC50 = 6.7 nM) and H1047R (IC50 = 5.6 nM) than wild-type PI3Kα. CH5132799 treated breast cnacer KPL-4 cells, which harbor the PIK3CA mutation, phosphorylation of Akt and its direct substrates, PRAS40 and FoxO1/3a and phosphorylation of downstream factors, including S6K, S6 and 4E-BP1, are effectively suppressed. Cancer cell lines harboring PIK3CA mutations are significantly sensitive to CH5132799 [1] In human tumor cell lines with PI3K pathway activation by mutation, CH5132799 shows potent antiproliferative activity [HCT116(CRC): IC50 = 0.20 lM, KPL-4(BC):13 IC50 = 0.032 lM, T-47D(BC): IC50 = 0.056 lM, SK-OV-3(Ovarian): IC50 = 0.12 lM]. CH5132799 effectively suppresses phosphorylation of AKT in KPL-4 cells. [2]
In Vivo CH5132799 shows potent in vivo antitumor activity in several different xenograft models with PIK3CA mutations. CH5132799 overcomes mTORC1 inhibition-mediated Akt activation and regrowth of xenograft tumor by long-term everolimus administration. [1] CH5132799 as a clinical candidate that shows excellent oral bioavailability (BA) (101% in mouse), human liver microsomal stability and in vivo antitumor activity in the PC-3 xenograft model (TGI: 101% at 25 mg/kg, po, q.d. × 11 days). CH5132799 exhibits good oral BA in mouse, rat, monkey and dog (F: 54.2–101%, Table 2). In a human breast cancer (KPL-4: PI3Ka H1047R) xenograft model in mice, oral treatment with CH5132799 (12.5 mg/kg, q.d.) shows strong tumor regression. The strong regression is maintained during the 6 week administration, even in the intermittent dosing schedule (q.d., 2 weeks on/1 week off; q.d., 5 days on/2 days off), suggesting that a flexible administration schedule can be applicable in the clinic. [2]
Clinical Trials CH5132799 is now in Phase 1 clinic trial fro the orally administration in human with advanced solid tumors.
Features
Combination Therapy
Description Combination with CH5132799 and trastuzumab, tumors disappears in the trastuzumab-insensitive breast cancer model with the PIK3CA mutation. [1]
Protocol
Kinase Assay [1]
PI3K Assay The E542K, E545K, and H1047R mutants of PI3Kα are prepared with an overlapped extension-polymerase chain reaction. Glutathione S-transferase-tagged PI3Kα mutants and His-tagged p85α are co-expressed with BAC-TO-BAC Baculovirus Expression System. The inhibitory activities of CH5132799 on PI3Kα (p110α/p85α), PI3Kβ(p110β/p85α), PI3Kδ (p110δ/p85α), PI3Kγ (p110γ), PI3KC2α, PI3KC2β, Vps34, and PI3Kα mutants are determined by Adapta Universal Kinase Assay Kit. Time-resolved fluorescence is measured with an EnVision HTS microplate reader. IC50 values are calculated using XLfit.
Cell Assay [1]
Cell Lines various cancer cell lines belonging to 4 types of cancer—breast, ovarian, prostate, and endometrial cancer—in which the PIK3CA mutation and PTEN deficiency are frequently found and in which RAS/RAF is rarely mutated
Concentrations 0 – 10μM
Incubation Time 4 days
Methods The cell lines are added to the wells of 96-well plates containing 0.076 to 10,000 nM CH5132799 and incubated at 37 °C. After 4 days of incubation, Cell Counting Kit-8 solution is added and, after incubation for several more hours, absorbance at 450 nm is measured with Microplate-Reader iMark. The antiproliferative activity is calculated by the formula (1- T/C) × 100 (%), in which T and C represent absorbance at 450 nm of the cells treated with CH5132799 (T) and that of untreated control cells (C). The IC50 values are calculated by using Microsoft Excel 2007.
Animal Study [1]
Animal Models A total of 4 × 106 to 1.2 × 107 cells are injected subcutaneously into the right flank of female BALB-nu/nu mice.
Formulation CH5132799 is dissolved in DMSO.
Doses 0.39, 0.78, 1.56, 3.13, 6.25, 12.5 and 25 mg/kg
Administration Orally administered once a day.
References
[1] Tanaka H, et al, Clin Cancer Res, 2011, 17(10), 3272-3281.
[2] Ohwada J, et al, Bioorg Med Chem Leff, 2011, 21(6), 1767-1772.

REFERENCES

REFERENCES

From Suppliers Google Scholar IconGoogle Scholar PubMed iconPubMed Google Books IconGoogle Books
  • Searching...Please wait...

PATENTS

PATENTS

PubChem iconPubChem Patent Google Patent Search IconGoogle Patent

INTERNET

INTERNET

Baidu iconBaidu google iconGoogle