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1032754-93-0

1032754-93-0 structure
1032754-93-0 structure
  • Name: GDC-0980(RG7422)
  • Chemical Name: (2S)-1-[4-[[2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl]piperazin-1-yl]-2-hydroxypropan-1-one
  • CAS Number: 1032754-93-0
  • Molecular Formula: C23H30N8O3S
  • Molecular Weight: 498.601
  • Catalog: Biochemical Inhibitor PI3K/Akt/mTOR inhibitor (PI3K/Akt/mTOR) PI3K inhibitor
  • Create Date: 2016-11-12 11:52:50
  • Modify Date: 2024-01-06 08:23:23
  • Apitolisib (GDC-0980) is a selective, potent, orally bioavailable Class I PI3 kinase and mTOR kinase (TORC1/2) inhibitor with IC50s of 5 nM/27 nM/7 nM/14 nM for PI3Kα/PI3Kβ/PI3Kδ/PI3Kγ, and with a Ki of 17 nM for mTOR.
Name (2S)-1-[4-[[2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl]piperazin-1-yl]-2-hydroxypropan-1-one
Synonyms GDC 0980
GDC-0980
GNE 390
(S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one
(2S)-1-(4-{[2-(2-Amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)thieno[3,2-d]pyrimidin-6-yl]methyl}-1-piperazinyl)-2-hydroxy-1-propanone
Apitolisib
1-Propanone, 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)thieno[3,2-d]pyrimidin-6-yl]methyl]-1-piperazinyl]-2-hydroxy-, (2S)-
[14C]-GDC-0980
GDC0980
RG7422
(2s)-1-(4-{[2-(2-Aminopyrimidin-5-Yl)-7-Methyl-4-(Morpholin-4-Yl)thieno[3,2-D]pyrimidin-6-Yl]methyl}piperazin-1-Yl)-2-Hydroxypropan-1-One
Apitolisib (GDC-0980)
Description Apitolisib (GDC-0980) is a selective, potent, orally bioavailable Class I PI3 kinase and mTOR kinase (TORC1/2) inhibitor with IC50s of 5 nM/27 nM/7 nM/14 nM for PI3Kα/PI3Kβ/PI3Kδ/PI3Kγ, and with a Ki of 17 nM for mTOR.
Related Catalog
Target

PI3Kα:5 nM (IC50)

PI3Kβ:27 nM (IC50)

PI3Kδ:7 nM (IC50)

PI3Kγ:14 nM (IC50)

mTOR:17 nM (Ki)

TORC1

TORC2

In Vitro Apitolisib (GDC-0980) is remarkably selective for several other members of the closely related PIKK family kinases: C2alpha IC50=1300 nM; C2beta IC50=7 94 nM; VPS34 IC50=2000 nM; PI4Kalpha >10 μM; PI4Kbeta >10 μM; DNA-PK Kiapp=623 nM, respectively[1]. A recent study shows that Apitolisib (GDC-0980) reduces cancer cell viability by inhibiting cell-cycle procession and inducing apoptosis with most potency in prostate (IC50 < 200 nM 50%), <500 nM 100%), breast (IC50 <200 nM 37%, <500 nM 78%) and NSCLC lines (IC50 <200 nM 29%, <500 nM 88%) and less potency in pancreatic (IC50 <200 nM 13%, <500 nM 67%) and melanoma cell lines (IC50 <200 nM 0%, <500 nM 33%)[2].
In Vivo Apitolisib (GDC-0980) (1 mg/kg, p.o.) demonstrats significant efficacy in mouse xenografts and is currently in phase I clinical trials for cancer. Clearance and PPB are low, and Apitolisib (GDC-0980) shows dose-proportional exposure from 5 mg/kg dosed in PEG to 50 mg/kg dosed in suspension in MCT, a finding attributed partially to the compound’s good solubility[1]. Apitolisib (GDC-0980) (5 mg/kg, p.o.) results in greater than 50% TGI in 15 of the 20 xenograft models. The difference in tumor response to Apitolisib (GDC-0980) treatment correlates with the duration of knockdown of pAkt/tAkt[2].
Kinase Assay Ten centimeter square dishes are seeded with 2 million cells in a volume of 10 mL followed by incubation at 37°C under 5% CO2 overnight (appr 16 hours). Cells are treated with the indicated concentration of GDC-0941, Apitolisib (GDC-0980), or mTOR1/2 inhibitor for the time indicated. Following treatment, cells are washed with cold PBS and lysed in 1X Cell Extraction Buffer, 1 mM PMSF, and Phosphatase Inhibitor Cocktails 1 and 2 are all needed. Protein concentration is determined using the Pierce BCA Protein Assay Kit. For immunoblots, equal protein amounts are separated by electrophoresis through NuPage Bis-Tris 10% gradient gels; proteins are transferred onto polyvinylidene difluoride membranes using the Criterion system and protocol.
Cell Assay Three hundred and eighty-four-well plates are seeded with 2,000 cells/well in a volume of 54 μL per well followed by incubation at 37°C under 5% CO2 overnight (appr 16 hours). Compounds are diluted in dimethyl sulfoxide to generate the desired stock concentrations then added in a volume of 6 μL per well. All treatments are tested in quadruplicate. After 4 days incubation, relative numbers of viable cells are estimated using CellTiter-Glo and total luminescence is measured on a Wallac Multilabel Reader. The concentration of drug resulting in 50% inhibition of cell viability (IC50) or 50% maximal effective concentration (EC50) is determined using Prism software. For cell lines that failed to achieve an IC50 the highest concentration tested (20 μM) is listed.
Animal Admin Human prostate cancer PC3 cells are resuspended in Hank’s Balanced Salt Solution and 3×106 cells implanted subcutaneously into the right hind flank of athymic nu/nu (nude) mice. Tumors are monitored until they reach a mean tumor volume of 150-200 mm3 prior to the initiation of dosing. MCF7.1 cells resuspended in a 1:1 mixture of Hank’s Buffered Salt Solution and Matrigel Basement Membrane Matrix are 5×106 subcutaneously implanted into the right hind flank of athymic nu/nu (nude) mice. Prior to cell inoculation, 17β-estradiol (0.36 mg/pellet, 60-day release, no. SE-121) are implanted into the dorsal shoulder blade area of each nude mouse. After implantation of cells, tumors are monitored until they reach a mean tumor volume of 250-350 mm3 prior to initiating dosing. Compound 2 is dissolved in 0.5% methylcellulose with 0.2% Tween-80 (MCT). Female nude (nu/nu) mice that are 6-8 weeks old and weighed 20-30 g are obtained from Charles River Laboratories. Tumor bearing mice are dosed daily for 14-21 days depending on the xenograft model with 100 μL of vehicle (MCT) or test agent orally.
References

[1]. Sutherlin DP, et al. Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J Med Chem, 2011, 54(21), 7579-7587.

[2]. Wallin JJ, et al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther, 2011, 10(12), 2426-2436.
Density 1.4±0.1 g/cm3
Boiling Point 718.6±70.0 °C at 760 mmHg
Molecular Formula C23H30N8O3S
Molecular Weight 498.601
Flash Point 388.4±35.7 °C
Exact Mass 498.216156
PSA 162.80000
LogP 0.45
Vapour Pressure 0.0±2.4 mmHg at 25°C
Index of Refraction 1.677
Storage condition -20℃
Precursor  3

DownStream  0


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