WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205467
CAS#: 1001264-89-6 (free base)
Description: Ipatasertib, also known as GDC-0068, is an orally bioavailable inhibitor of the serine/threonine protein kinase Akt (protein kinase B) with potential antineoplastic activity. Akt inhibitor GDC-0068 binds to and inhibits the activity of Akt in a non-ATP-competitive manner, which may result in the inhibition of the PI3K/Akt signaling pathway and tumor cell proliferation and the induction of tumor cell apoptosis.
MedKoo Cat#: 205467
Name: Ipatasertib (GDC-0068)
CAS#: 1001264-89-6 (free base)
Chemical Formula: C24H32ClN5O2
Exact Mass: 457.22445
Molecular Weight: 458.0
Elemental Analysis: C, 62.94; H, 7.04; Cl, 7.74; N, 15.29; O, 6.99
Related CAS #: 1001264-89-6 (free base) 1489263-16-2 (HCl) 1396257-94-5 (2HCl) 1491138-23-8 (besylate) 1491138-24-9 (tosylate)
Synonym: GDC0068; GDC-0068; GDC 0068; RG7440; RG-7440; RG 7440; Ipatasertib
IUPAC/Chemical Name: (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one
InChi Key: GRZXWCHAXNAUHY-NSISKUIASA-N
InChi Code: InChI=1S/C24H32ClN5O2/c1-15(2)26-13-19(17-4-6-18(25)7-5-17)24(32)30-10-8-29(9-11-30)23-21-16(3)12-20(31)22(21)27-14-28-23/h4-7,14-16,19-20,26,31H,8-13H2,1-3H3/t16-,19-,20-/m1/s1
SMILES Code: O=C(N1CCN(C2=C([C@H](C)C[C@H]3O)C3=NC=N2)CC1)[C@@H](C4=CC=C(Cl)C=C4)CNC(C)C
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 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: | Ipatasertib (GDC-0068) is an ATP-competitive pan-Akt inhibitor with IC50s of 5, 18 and 8 nM for Akt1, Akt2 and Akt3, respectively. |
| In vitro activity: | In contrast, LREX, which is poised to upregulate GR expression to achieve enzalutamide resistance (8), was confirmed to be completely resistant to enzalutamide but had a marked response to ipatasertib (Fig. 1A, third panel). Consistent with its mechanism of action, the effect of ipatasertib on cell viability correlated with inhibition of AKT signaling, which is manifest as an increase in AKT phosphorylation (due to its ability to protect against phosphatases) and decrease in phosphorylation of downstream targets (Fig. 1B). As expected, enzalutamide decreased AR activity, demonstrated by decreased expression of canonical AR targets PSA and NKX3 in C4-2 and LREX cells, though not in 22RV1 cells, which express the AR variant AR-V7. Interestingly, C4-2 and LREX had increased expression of these canonical AR targets in the presence of ipatasertib. To determine whether ipatasertib has an anticancer effect in hormone-sensitive prostate cancer (HSPC), this study tested its effect in the well-characterized HSPC cell lines LNCaP and LAPC4. Both models of HSPC were more sensitive to ipatasertib than to androgen withdrawal (Supplementary Fig. S1A). Reference: Mol Cancer Ther. 2020 Jul;19(7):1436-1447. https://mct.aacrjournals.org/content/19/7/1436.long |
| In vivo activity: | In the PIK3CA-MT MDA-MB-361 BCBM tumor model, GDC-0068 resulted in a significant inhibition of tumor growth measured by BLI in treated mice, whereas in contrast, sham-treated tumors continued to grow more rapidly (Figure 4A–C). No differences in tumor growth and survival were detected in MDA-MB-231 BrM2 intracranial tumors over the course of treatment (Supplementary Figure 2). Treatment with GDC-0068 led to a significant inhibition in the MDA-MB-361 tumor bearing mice compared with sham (mixed effect model, effect of treatment at day 77: P < 0.0001) (Figure 4B). Furthermore, treatment with GDC-0068 resulted in a significant survival benefit (log-rank test, P = 0.0008), with a median survival of 109 days in treated mice versus 82.5 days in mice receiving sham treatment (Figure 4D). To evaluate GDC-0068–induced phosphorylation inhibition of PI3K/Akt/mTOR pathway downstream targets, expression of p-PRAS40 and p-S6 ribosomal protein was analyzed with immunohistochemistry. In accordance with the previous in vitro and in vivo results, GDC-0068 treated tumors in MDA-MB-361 tumor bearing mice revealed reduced immunostaining of p-S6 ribosomal protein compared with tumors of the sham cohort (Figure 4E), but no such effect was seen in the PIK3CA-mutant cell line MDA-MB-231 BrM2 (Supplementary Figure 2). Reference: Neuro Oncol. 2019 Nov; 21(11): 1401–1411. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827829/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 45.0 | 98.25 | |
| DMF | 25.0 | 54.59 | |
| DMF:PBS (pH 7.2) (1:1) | 0.5 | 1.09 | |
| Ethanol | 56.0 | 122.27 | |
| Water | 10.0 | 21.83 |
The following data is based on the product molecular weight 458.0 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: | 1. Adelaiye-Ogala R, Gryder BE, Nguyen YTM, Alilin AN, Grayson AR, Bajwa W, Jansson KH, Beshiri ML, Agarwal S, Rodriguez-Nieves JA, Capaldo B, Kelly K, VanderWeele DJ. Targeting the PI3K/AKT Pathway Overcomes Enzalutamide Resistance by Inhibiting Induction of the Glucocorticoid Receptor. Mol Cancer Ther. 2020 Jul;19(7):1436-1447. doi: 10.1158/1535-7163.MCT-19-0936. Epub 2020 May 5. PMID: 32371590. 2. Sun L, Huang Y, Liu Y, Zhao Y, He X, Zhang L, Wang F, Zhang Y. Ipatasertib, a novel Akt inhibitor, induces transcription factor FoxO3a and NF-κB directly regulates PUMA-dependent apoptosis. Cell Death Dis. 2018 Sep 5;9(9):911. doi: 10.1038/s41419-018-0943-9. PMID: 30185800; PMCID: PMC6125489. 3. Ippen FM, Grosch JK, Subramanian M, Kuter BM, Liederer BM, Plise EG, Mora JL, Nayyar N, Schmidt SP, Giobbie-Hurder A, Martinez-Lage M, Carter SL, Cahill DP, Wakimoto H, Brastianos PK. Targeting the PI3K/Akt/mTOR pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases. Neuro Oncol. 2019 Nov 4;21(11):1401-1411. doi: 10.1093/neuonc/noz105. PMID: 31173106; PMCID: PMC6827829. 4. Lin J, Sampath D, Nannini MA, Lee BB, Degtyarev M, Oeh J, Savage H, Guan Z, Hong R, Kassees R, Lee LB, Risom T, Gross S, Liederer BM, Koeppen H, Skelton NJ, Wallin JJ, Belvin M, Punnoose E, Friedman LS, Lin K. Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res. 2013 Apr 1;19(7):1760-72. doi: 10.1158/1078-0432.CCR-12-3072. Epub 2013 Jan 3. PMID: 23287563. |
| In vitro protocol: | 1. Adelaiye-Ogala R, Gryder BE, Nguyen YTM, Alilin AN, Grayson AR, Bajwa W, Jansson KH, Beshiri ML, Agarwal S, Rodriguez-Nieves JA, Capaldo B, Kelly K, VanderWeele DJ. Targeting the PI3K/AKT Pathway Overcomes Enzalutamide Resistance by Inhibiting Induction of the Glucocorticoid Receptor. Mol Cancer Ther. 2020 Jul;19(7):1436-1447. doi: 10.1158/1535-7163.MCT-19-0936. Epub 2020 May 5. PMID: 32371590. 2. Sun L, Huang Y, Liu Y, Zhao Y, He X, Zhang L, Wang F, Zhang Y. Ipatasertib, a novel Akt inhibitor, induces transcription factor FoxO3a and NF-κB directly regulates PUMA-dependent apoptosis. Cell Death Dis. 2018 Sep 5;9(9):911. doi: 10.1038/s41419-018-0943-9. PMID: 30185800; PMCID: PMC6125489. |
| In vivo protocol: | 1. Ippen FM, Grosch JK, Subramanian M, Kuter BM, Liederer BM, Plise EG, Mora JL, Nayyar N, Schmidt SP, Giobbie-Hurder A, Martinez-Lage M, Carter SL, Cahill DP, Wakimoto H, Brastianos PK. Targeting the PI3K/Akt/mTOR pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases. Neuro Oncol. 2019 Nov 4;21(11):1401-1411. doi: 10.1093/neuonc/noz105. PMID: 31173106; PMCID: PMC6827829. 2. Lin J, Sampath D, Nannini MA, Lee BB, Degtyarev M, Oeh J, Savage H, Guan Z, Hong R, Kassees R, Lee LB, Risom T, Gross S, Liederer BM, Koeppen H, Skelton NJ, Wallin JJ, Belvin M, Punnoose E, Friedman LS, Lin K. Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res. 2013 Apr 1;19(7):1760-72. doi: 10.1158/1078-0432.CCR-12-3072. Epub 2013 Jan 3. PMID: 23287563. |
1: Lin J, Sampath D, Nannini MA, Lee BB, Degtyarev M, Oeh J, Savage H, Guan Z, Hong R, Kassees R, Lee LB, Risom T, Gross S, Liederer BM, Koeppen H, Skelton NJ, Wallin JJ, Belvin M, Punnoose E, Friedman LS, Lin K. Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res. 2013 Apr 1;19(7):1760-72. doi: 10.1158/1078-0432.CCR-12-3072. PubMed PMID: 23287563.
2: Yan Y, Serra V, Prudkin L, Scaltriti M, Murli S, Rodríguez O, Guzman M, Sampath D, Nannini M, Xiao Y, Wagle MC, Wu JQ, Wongchenko M, Hampton G, Ramakrishnan V, Lackner MR, Saura C, Roda D, Cervantes A, Tabernero J, Patel P, Baselga J. Evaluation and clinical analyses of downstream targets of the Akt inhibitor GDC-0068. Clin Cancer Res. 2013 Dec 15;19(24):6976-86. doi: 10.1158/1078-0432.CCR-13-0978. PubMed PMID: 24141624.
3: Blake JF, Xu R, Bencsik JR, Xiao D, Kallan NC, Schlachter S, Mitchell IS, Spencer KL, Banka AL, Wallace EM, Gloor SL, Martinson M, Woessner RD, Vigers GP, Brandhuber BJ, Liang J, Safina BS, Li J, Zhang B, Chabot C, Do S, Lee L, Oeh J, Sampath D, Lee BB, Lin K, Liederer BM, Skelton NJ. Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors. J Med Chem. 2012 Sep 27;55(18):8110-27. PubMed PMID: 22934575.
4: Mou L, Cui T, Liu W, Zhang H, Cai Z, Lu S, Gao G. Microsecond molecular dynamics simulations provide insight into the ATP-competitive inhibitor-induced allosteric protection of Akt kinase phosphorylation. Chem Biol Drug Des. 2016 Oct 31. doi: 10.1111/cbdd.12895. [Epub ahead of print] PubMed PMID: 27797456.
5: Tao JJ, Castel P, Radosevic-Robin N, Elkabets M, Auricchio N, Aceto N, Weitsman G, Barber P, Vojnovic B, Ellis H, Morse N, Viola-Villegas NT, Bosch A, Juric D, Hazra S, Singh S, Kim P, Bergamaschi A, Maheswaran S, Ng T, Penault-Llorca F, Lewis JS, Carey LA, Perou CM, Baselga J, Scaltriti M. Antagonism of EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer. Sci Signal. 2014 Mar 25;7(318):ra29. doi: 10.1126/scisignal.2005125. PubMed PMID: 24667376; PubMed Central PMCID: PMC4283215.
6: Wehrenberg-Klee E, Turker NS, Heidari P, Larimer B, Juric D, Baselga J, Scaltriti M, Mahmood U. Differential Receptor Tyrosine Kinase PET Imaging for Therapeutic Guidance. J Nucl Med. 2016 Sep;57(9):1413-9. doi: 10.2967/jnumed.115.169417. PubMed PMID: 27081168.
7: Saura C, Roda D, Roselló S, Oliveira M, Macarulla T, Pérez-Fidalgo JA, Morales-Barrera R, Sanchis-García JM, Musib L, Budha N, Zhu J, Nannini M, Chan WY, Sanabria Bohórquez SM, Meng RD, Lin K, Yan Y, Patel P, Baselga J, Tabernero J, Cervantes A. A First-in-Human Phase I Study of the ATP-Competitive AKT Inhibitor Ipatasertib Demonstrates Robust and Safe Targeting of AKT in Patients with Solid Tumors. Cancer Discov. 2017 Jan;7(1):102-113. doi: 10.1158/2159-8290.CD-16-0512. PubMed PMID: 27872130.
8: Yu B, Liu L, Sun H, Chen Y. Long noncoding RNA AK056155 involved in the development of Loeys-Dietz syndrome through AKT/PI3K signaling pathway. Int J Clin Exp Pathol. 2015 Sep 1;8(9):10768-75. PubMed PMID: 26617788; PubMed Central PMCID: PMC4637603.
9: Yang G, Murashige DS, Humphrey SJ, James DE. A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation. Cell Rep. 2015 Aug 11;12(6):937-43. doi: 10.1016/j.celrep.2015.07.016. PubMed PMID: 26235620.
Activation of the PI3K/Akt signaling pathway is frequently associated with tumorigenesis and dysregulated PI3K/Akt signaling may contribute to tumor resistance to a variety of antineoplastic agents.
