GDC-0980 (Apitolisib)
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MedKoo CAT#: 205470

CAS#: 1032754-93-0

Description: Apitolisib, also known as GDC-0980 and RG7422; or GNE390, is a dual PI3 kinase/mTOR inhibitor, is also a n orally available agent targeting phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) kinase in the PI3K/mTOR signaling pathway, with potential antineoplastic activity. PI3K/mTOR kinase inhibitor GDC-0980 inhibits both PI3K kinase and mTOR kinase, which may result in tumor cell apoptosis and growth inhibition of cancer cells overexpressing PI3K/mTOR.


Chemical Structure

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GDC-0980 (Apitolisib)
CAS# 1032754-93-0

Theoretical Analysis

MedKoo Cat#: 205470
Name: GDC-0980 (Apitolisib)
CAS#: 1032754-93-0
Chemical Formula: C23H30N8O3S
Exact Mass: 498.21616
Molecular Weight: 498.6
Elemental Analysis: C, 55.40; H, 6.06; N, 22.47; O, 9.63; S, 6.43

Price and Availability

Size Price Availability Quantity
25.0mg USD 150.0 Same day
50.0mg USD 250.0 Same day
100.0mg USD 450.0 Same day
200.0mg USD 850.0 Same day
500.0mg USD 1850.0 Same day
1.0g USD 2950.0 Same day
2.0g USD 5350.0 Same day
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Synonym: GDC0980; GDC-0980; GDC 0980; RG7422; RG-7422; RG 7422; GNE 390; GNE-390; GNE390; Apitolisib

IUPAC/Chemical Name: (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.

InChi Key: YOVVNQKCSKSHKT-HNNXBMFYSA-N

InChi Code: InChI=1S/C23H30N8O3S/c1-14-17(13-29-3-5-31(6-4-29)22(33)15(2)32)35-19-18(14)27-20(16-11-25-23(24)26-12-16)28-21(19)30-7-9-34-10-8-30/h11-12,15,32H,3-10,13H2,1-2H3,(H2,24,25,26)/t15-/m0/s1

SMILES Code: C[C@H](O)C(N1CCN(CC2=C(C)C3=NC(C4=CN=C(N)N=C4)=NC(N5CCOCC5)=C3S2)CC1)=O

Appearance: white 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 in water

Shelf Life: >2 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

Biological target: Apitolisib (GDC-0980; GNE 390; RG 7422) is a 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.
In vitro activity: GDC-0980 is a potent small-molecule inhibitor of class I PI3K isoforms and mTOR kinase and displays excellent selectivity against a large panel of other kinases, including closely related family members DNA-PK, VPS34, c2alpha, and c2beta (Fig. 1; ref. 19). This study assessed a panel of breast, non-small cell lung, colon, pancreatic, melanoma, and prostate cancer cell lines in cell viability experiments to profile the activity of GDC-0980 in vitro (Fig. 1). GDC-0980 was most effective in prostate (IC50 < 200 nmol/L 50%), <500 nmol/L 100%), breast (IC50 <200 nmol/L 37%, <500 nmol/L 78%) and NSCLC lines (IC50 <200 nmol/L 29%, <500 nmol/L0 88%), and was less effective in pancreatic (IC50 <200 nmol/L 13%, <500 nmol/L 67%) and melanoma cell lines (IC50 <200 nmol/L 0%, <500 nmol/L 33%). Taken together, GDC-0980 had broad cellular activity with potency below 500 nmol/L in 124 out of the 167 cell lines tested. Reference: Mol Cancer Ther. 2011 Dec;10(12):2426-36. https://pubmed.ncbi.nlm.nih.gov/21998291/
In vivo activity: GDC-0980 was administered orally, daily, to MCF7-neo/HER2 tumor-bearing mice at doses ranging from 0.25 to 7.5 mg/kg. Tumor growth inhibition results are presented in Fig. 7C. The inhibition of the MCF7-neo/HER2 tumor growth appeared to be dose dependent. An indirect response model was fitted to the tumor data from all of the doses (eq. 1) and appeared to describe them adequately. The comparison between the observed TVs and the model predictions is presented in Fig. 7D. The estimates of the pharmacodynamic parameters describing MCF7-neo/HER2 tumor growth and reduction effect by GDC-0980 are presented in Table 8. Reference: Drug Metab Dispos. 2012 Sep;40(9):1785-96. https://pubmed.ncbi.nlm.nih.gov/22696419/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 19.76 39.63
DMSO:PBS (pH 7.2) (1:5) 0.15 0.3
DMF 25.0 50.14

Preparing Stock Solutions

The following data is based on the product molecular weight 498.6 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.

Recalculate based on batch purity %
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: 1. Wallin JJ, Edgar KA, Guan J, Berry M, Prior WW, Lee L, Lesnick JD, Lewis C, Nonomiya J, Pang J, Salphati L, Olivero AG, Sutherlin DP, O'Brien C, Spoerke JM, Patel S, Lensun L, Kassees R, Ross L, Lackner MR, Sampath D, Belvin M, Friedman LS. 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 Dec;10(12):2426-36. doi: 10.1158/1535-7163.MCT-11-0446. Epub 2011 Oct 13. PMID: 21998291. 2. Sutherlin DP, Bao L, Berry M, Castanedo G, Chuckowree I, Dotson J, Folks A, Friedman L, Goldsmith R, Gunzner J, Heffron T, Lesnick J, Lewis C, Mathieu S, Murray J, Nonomiya J, Pang J, Pegg N, Prior WW, Rouge L, Salphati L, Sampath D, Tian Q, Tsui V, Wan NC, Wang S, Wei B, Wiesmann C, Wu P, Zhu BY, Olivero A. 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 Nov 10;54(21):7579-87. doi: 10.1021/jm2009327. Epub 2011 Oct 7. PMID: 21981714. 3. Salphati L, Pang J, Plise EG, Lee LB, Olivero AG, Prior WW, Sampath D, Wong S, Zhang X. Preclinical assessment of the absorption and disposition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor GDC-0980 and prediction of its pharmacokinetics and efficacy in human. Drug Metab Dispos. 2012 Sep;40(9):1785-96. doi: 10.1124/dmd.112.046052. Epub 2012 Jun 13. PMID: 22696419. 4. Wallin JJ, Edgar KA, Guan J, Berry M, Prior WW, Lee L, Lesnick JD, Lewis C, Nonomiya J, Pang J, Salphati L, Olivero AG, Sutherlin DP, O'Brien C, Spoerke JM, Patel S, Lensun L, Kassees R, Ross L, Lackner MR, Sampath D, Belvin M, Friedman LS. 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 Dec;10(12):2426-36. doi: 10.1158/1535-7163.MCT-11-0446. Epub 2011 Oct 13. PMID: 21998291.
In vitro protocol: 1. Wallin JJ, Edgar KA, Guan J, Berry M, Prior WW, Lee L, Lesnick JD, Lewis C, Nonomiya J, Pang J, Salphati L, Olivero AG, Sutherlin DP, O'Brien C, Spoerke JM, Patel S, Lensun L, Kassees R, Ross L, Lackner MR, Sampath D, Belvin M, Friedman LS. 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 Dec;10(12):2426-36. doi: 10.1158/1535-7163.MCT-11-0446. Epub 2011 Oct 13. PMID: 21998291. 2. Sutherlin DP, Bao L, Berry M, Castanedo G, Chuckowree I, Dotson J, Folks A, Friedman L, Goldsmith R, Gunzner J, Heffron T, Lesnick J, Lewis C, Mathieu S, Murray J, Nonomiya J, Pang J, Pegg N, Prior WW, Rouge L, Salphati L, Sampath D, Tian Q, Tsui V, Wan NC, Wang S, Wei B, Wiesmann C, Wu P, Zhu BY, Olivero A. 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 Nov 10;54(21):7579-87. doi: 10.1021/jm2009327. Epub 2011 Oct 7. PMID: 21981714.
In vivo protocol: 1. Salphati L, Pang J, Plise EG, Lee LB, Olivero AG, Prior WW, Sampath D, Wong S, Zhang X. Preclinical assessment of the absorption and disposition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor GDC-0980 and prediction of its pharmacokinetics and efficacy in human. Drug Metab Dispos. 2012 Sep;40(9):1785-96. doi: 10.1124/dmd.112.046052. Epub 2012 Jun 13. PMID: 22696419. 2. Wallin JJ, Edgar KA, Guan J, Berry M, Prior WW, Lee L, Lesnick JD, Lewis C, Nonomiya J, Pang J, Salphati L, Olivero AG, Sutherlin DP, O'Brien C, Spoerke JM, Patel S, Lensun L, Kassees R, Ross L, Lackner MR, Sampath D, Belvin M, Friedman LS. 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 Dec;10(12):2426-36. doi: 10.1158/1535-7163.MCT-11-0446. Epub 2011 Oct 13. PMID: 21998291.

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1: English DP, Bellone S, Cocco E, Bortolomai I, Pecorelli S, Lopez S, Silasi DA, Schwartz PE, Rutherford T, Santin AD. Oncogenic PIK3CA gene mutations and HER2/neu gene amplifications determine the sensitivity of uterine serous carcinoma cell lines to GDC-0980, a selective inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2). Am J Obstet Gynecol. 2013 Nov;209(5):465.e1-9. doi: 10.1016/j.ajog.2013.07.020. Epub 2013 Jul 24. PubMed PMID: 23891627.

2: Salphati L, Pang J, Plise EG, Lee LB, Olivero AG, Prior WW, Sampath D, Wong S, Zhang X. Preclinical assessment of the absorption and disposition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor GDC-0980 and prediction of its pharmacokinetics and efficacy in human. Drug Metab Dispos. 2012 Sep;40(9):1785-96. doi: 10.1124/dmd.112.046052. Epub 2012 Jun 13. PubMed PMID: 22696419.

3: Wallin JJ, Edgar KA, Guan J, Berry M, Prior WW, Lee L, Lesnick JD, Lewis C, Nonomiya J, Pang J, Salphati L, Olivero AG, Sutherlin DP, O'Brien C, Spoerke JM, Patel S, Lensun L, Kassees R, Ross L, Lackner MR, Sampath D, Belvin M, Friedman LS. 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 Dec;10(12):2426-36. doi: 10.1158/1535-7163.MCT-11-0446. Epub 2011 Oct 13. PubMed PMID: 21998291.

4: Sutherlin DP, Bao L, Berry M, Castanedo G, Chuckowree I, Dotson J, Folks A, Friedman L, Goldsmith R, Gunzner J, Heffron T, Lesnick J, Lewis C, Mathieu S, Murray J, Nonomiya J, Pang J, Pegg N, Prior WW, Rouge L, Salphati L, Sampath D, Tian Q, Tsui V, Wan NC, Wang S, Wei B, Wiesmann C, Wu P, Zhu BY, Olivero A. 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 Nov 10;54(21):7579-87. doi: 10.1021/jm2009327. Epub 2011 Oct 7. PubMed PMID: 21981714.



Additional Information

GCD-0980 is potent across PI3K class I isoforms with IC(50)s of 5, 27, 7, and 14 nM for PI3Kα, β, δ, and γ, respectively, inhibits mTOR with a K(i) of 17 nM yet is highly selective versus a large panel of kinases including others in the PIKK family. On the basis of the cell potency, low clearance in mouse, and high free fraction, 2 demonstrated significant efficacy in mouse xenografts when dosed as low as 1 mg/kg orally and is currently in phase I clinical trials for cancer. [source: J Med Chem. 2011 Nov 10;54(21):7579-87.]