WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205884
CAS#: 1056901-62-2
Description: AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which shows a distinct mechanism of action from other AKT inhibitors. AT13148 is currently being developed by Astex Pharmaceuticals. AT131148 was identified utilizing high-throughput X-ray crystallography and fragment-based lead discovery techniques. AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK and SGK substrate phosphorylation and induction of apoptosis in both a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects both in vitro and in vivo.
MedKoo Cat#: 205884
Name: AT13148
CAS#: 1056901-62-2
Chemical Formula: C17H16ClN3O
Exact Mass: 313.09819
Molecular Weight: 313.78
Elemental Analysis: C, 65.07; H, 5.14; Cl, 11.30; N, 13.39; O, 5.10
Related CAS #: 1056901-62-2 1056901-67-7 (R-isomer) 857532-13-9 (racemic)
Synonym: AT-13148; AT 13148; AT13148; AT13148 hydrochloride; AT13148 HCl
IUPAC/Chemical Name: (S)-1-(4-(1H-pyrazol-4-yl)phenyl)-2-amino-1-(4-chlorophenyl)ethanol
InChi Key: IIRWNGPLJQXWFJ-KRWDZBQOSA-N
InChi Code: InChI=1S/C17H16ClN3O/c18-16-7-5-15(6-8-16)17(22,11-19)14-3-1-12(2-4-14)13-9-20-21-10-13/h1-10,22H,11,19H2,(H,20,21)/t17-/m0/s1
SMILES Code: ClC1=CC=C([C@](C2=CC=C(C3=CNN=C3)C=C2)(O)CN)C=C1
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: | AT13148 is an ATP-competitive, multi-AGC kinase inhibitor with IC50s of 38 nM/402 nM/50 nM, 8 nM, 3 nM, and 6 nM/4 nM for Akt1/2/3, p70S6K, PKA, and ROCKI/II, respectively. |
| In vitro activity: | AT13148 potently inhibited proliferation with GI50 values of 1.5 to 3.8 μmol/L across a selected panel of cancer cell lines (Supplementary Table S3) representing common human malignancies with deregulation of PI3K-AKT-mTOR or RAS-RAF pathways. The effect of 1-hour exposure to AT13148 on AKT and p70S6K signaling was initially explored in PTEN-deficient U87MG glioblastoma cells (Fig. 2A). Marked induction of pSer473 AKT occurred at all concentrations. Nevertheless, phosphorylation of the 2 AKT substrates GSK3β and PRAS40 was inhibited at AT13148 concentrations >1 and 5 μmol/L AT13148, respectively. Reference: Clin Cancer Res. 2012 Jul 15;18(14):3912-23. https://clincancerres.aacrjournals.org/content/18/14/3912.long |
| In vivo activity: | In contrast, in AT13148 treated mice, tumor cells homed and grew on the pancreas, but a clearly demarcated border was consistently observed between tumor and normal tissue (Fig. 6A lower panels). When the area of the invasive region, in which tumor cells were intermixed with normal pancreas cells, was expressed as a percentage of the total pancreas for each condition, there was a significant decrease in the invasive region for AT13148 treated mice (Fig. 6A), which approached significance for the less potent ROCK inhibitor fasudil treated mice (Fig. 6B). To determine whether the anti-invasive effect of AT13148 treatment was due to decreased proliferation, mice were injected with bromodeoxyuridine (BrdU) 2 h before sacrifice, and then tissues were stained with anti-BrdU antibody (Fig. 6C). Counting the percentage of BrdU positive tumor cells indicated that there was no effect of AT13148 on proliferation (Fig. 6D), indicating that reduced invasion of pancreatic tissue was a direct effect on invasive behaviors. Reference: Cancer Res. 2018 Jun 15; 78(12): 3321–3336. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005347/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 47.33 | 150.84 | |
| DMSO:PBS (pH 7.2) (1:2) | 0.33 | 1.05 | |
| DMF | 30.0 | 95.61 |
The following data is based on the product molecular weight 313.78 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. Sadok A, McCarthy A, Caldwell J, Collins I, Garrett MD, Yeo M, Hooper S, Sahai E, Kuemper S, Mardakheh FK, Marshall CJ. Rho kinase inhibitors block melanoma cell migration and inhibit metastasis. Cancer Res. 2015 Jun 1;75(11):2272-84. doi: 10.1158/0008-5472.CAN-14-2156. Epub 2015 Apr 3. PMID: 25840982. 2. Yap TA, Walton MI, Grimshaw KM, Te Poele RH, Eve PD, Valenti MR, de Haven Brandon AK, Martins V, Zetterlund A, Heaton SP, Heinzmann K, Jones PS, Feltell RE, Reule M, Woodhead SJ, Davies TG, Lyons JF, Raynaud FI, Eccles SA, Workman P, Thompson NT, Garrett MD. AT13148 is a novel, oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity. Clin Cancer Res. 2012 Jul 15;18(14):3912-23. doi: 10.1158/1078-0432.CCR-11-3313. Epub 2012 Jul 10. PMID: 22781553. 3. Rath N, Munro J, Cutiongco MF, Jagiełło A, Gadegaard N, McGarry L, Unbekandt M, Michalopoulou E, Kamphorst JJ, Sumpton D, Mackay G, Vennin C, Pajic M, Timpson P, Olson MF. Rho Kinase Inhibition by AT13148 Blocks Pancreatic Ductal Adenocarcinoma Invasion and Tumor Growth. Cancer Res. 2018 Jun 15;78(12):3321-3336. doi: 10.1158/0008-5472.CAN-17-1339. Epub 2018 Apr 18. PMID: 29669760; PMCID: PMC6005347. |
| In vitro protocol: | 1. Sadok A, McCarthy A, Caldwell J, Collins I, Garrett MD, Yeo M, Hooper S, Sahai E, Kuemper S, Mardakheh FK, Marshall CJ. Rho kinase inhibitors block melanoma cell migration and inhibit metastasis. Cancer Res. 2015 Jun 1;75(11):2272-84. doi: 10.1158/0008-5472.CAN-14-2156. Epub 2015 Apr 3. PMID: 25840982. 2. Yap TA, Walton MI, Grimshaw KM, Te Poele RH, Eve PD, Valenti MR, de Haven Brandon AK, Martins V, Zetterlund A, Heaton SP, Heinzmann K, Jones PS, Feltell RE, Reule M, Woodhead SJ, Davies TG, Lyons JF, Raynaud FI, Eccles SA, Workman P, Thompson NT, Garrett MD. AT13148 is a novel, oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity. Clin Cancer Res. 2012 Jul 15;18(14):3912-23. doi: 10.1158/1078-0432.CCR-11-3313. Epub 2012 Jul 10. PMID: 22781553. |
| In vivo protocol: | 1. Rath N, Munro J, Cutiongco MF, Jagiełło A, Gadegaard N, McGarry L, Unbekandt M, Michalopoulou E, Kamphorst JJ, Sumpton D, Mackay G, Vennin C, Pajic M, Timpson P, Olson MF. Rho Kinase Inhibition by AT13148 Blocks Pancreatic Ductal Adenocarcinoma Invasion and Tumor Growth. Cancer Res. 2018 Jun 15;78(12):3321-3336. doi: 10.1158/0008-5472.CAN-17-1339. Epub 2018 Apr 18. PMID: 29669760; PMCID: PMC6005347. 2. Yap TA, Walton MI, Grimshaw KM, Te Poele RH, Eve PD, Valenti MR, de Haven Brandon AK, Martins V, Zetterlund A, Heaton SP, Heinzmann K, Jones PS, Feltell RE, Reule M, Woodhead SJ, Davies TG, Lyons JF, Raynaud FI, Eccles SA, Workman P, Thompson NT, Garrett MD. AT13148 is a novel, oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity. Clin Cancer Res. 2012 Jul 15;18(14):3912-23. doi: 10.1158/1078-0432.CCR-11-3313. Epub 2012 Jul 10. PMID: 22781553. |
1: Yap TA, Walton MI, Grimshaw KM, Te Poele RH, Eve PD, Valenti MR, de Haven Brandon AK, Martins V, Zetterlund A, Heaton SP, Heinzmann K, Jones PS, Feltell RE, Reule M, Woodhead SJ, Davies TG, Lyons JF, Raynaud FI, Eccles SA, Workman P, Thompson NT, Garrett MD. AT13148 is a novel, oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity. Clin Cancer Res. 2012 Jul 15;18(14):3912-23. doi: 10.1158/1078-0432.CCR-11-3313. Epub 2012 Jul 10. PubMed PMID: 22781553.
AT13148 is an orally active small molecule inhibitor of PKB/Akt and p70S6 kinase, key enzymes in the PI3K/PKB/mTOR tumor cell survival pathway. AT13148 has the potential to be a very effective inhibitor of AKT dependent tumors. In September 2008 Astex announced a partnership with Cancer Research UK and CRT to take AT13148 into development under the charity's Clinical Development Partnerships (CDP) program. Under the terms of this agreement, Cancer Research UK's Drug Development Office has carried out further development work on the agent, some of which is done in collaboration with the ICR. CRUK plans to commence phase 1 clinical trials of AT13148 at the Royal Marsden Hospital in the UK during 2012. (source:http://astx.com/pipeline/products/clinical).
