Inhibitors of the PI3K/Akt/mTOR Signalling Pathway

Selleck Chemicals is one of the worlds leading suppliers of high-performance inhibitors and reference compounds for non-clinical research fields focusing on signaling pathways such as MAPK, PI3K/Akt, JAK/STAT and apoptosis.

PI3K/Akt/mTOR dependent signaling pathway contributes to many cellular processes such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which might be involved in oncogenesis under certain situations[1]. When a growth factor or ligand such as human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor(EGFR), insulin-like growth factor receptor and vascular endothelial growth factor receptor, binds to the tyrosine kinase receptors (RTK),  the PI3K is activated by G protein-coupled receptors[2]. Activated PI3K generates phosphatidylinositol-3,4,5-triphosphate, which recruits PDK1 and Akt serine/threonine kinase at the plasma membrane. This results in the activation of Akt which activates multiple downstream targets, including the mTOR pathway.

SPECIFIC INHIBITORS OF PI3KI

In the following work, isoform-selective PI3K inhibitors were reported. PI 103 is able to inhibit both p110a and mTOR in glioma cells [3]. A Phase I study showed that a selective inhibitor of p110δ called CAL 101 could be helpful with the treatment of hematologic malignancies in patients [4]

SPECIFIC INHIBITORS OF AKT

Akt is another potential target for the therapy of cancer for the reason that Akt is one of the most important downstream molecule of PI3Ks. There are three isoforms of Akt: Akt1, Akt2 and Akt3. A dual inhibitor of Akt1 and Akt2 named Akti 1/2 showed potent anti tumor activity in tumor xenograft models. MK2206, the analog of Akti 1/2, is now in the Phase I clinical trial for the treatment of locally advanced or metastatic solid tumors and a Phase II study in advanced hepatocellular carcinoma [5;6].

SPECIFIC INHIBITORS OF mTOR

As one of the key components of PI3K pathway, mTOR exists in two different complexes, mTORC1 and mTORC2. Rapamycin or sirolimus (Rapamune®; Wyeth, NJ, USA), which mainly inhibits the activity of mTORC1, recently presented antitumor effects [7;8].

Under some conditions, inhibiting more than one target of PI3K pathway might lead to better effect. BEZ235, dual PI3K/mTOR inhibitor, inhibits Class I PI3K isoforms and mTOR kinase activity by binding to the ATP-binding pocket of PI3K. It has strong anti-proliferative effect on tumor xenografts and is now under Phase I/II clinical trials for breast cancer and endometrial cancer [5].

Selleck provides 2 unique inhibitor kits for a range of PI3K subtypes and the PI3K/Akt/mTOR signaling pathway

PI3K Inhibitor Kit – K1010

A unique collection of 7 inhibitors for a range of PI3K subtypes supplied as lyophilized powder

• S1009 – BEZ235 (NVP-BEZ235)
• S2636 – A66
• S1169 – TGX-221
• S1410 – AS-605240
• S2226 – CAL-101 (GS-1101)
• S1038 – PI-103
• S2767 – 3-Methyladenine

PI3K/Akt/mTOR Pathway Inhibitor Kit – K1020

A unique collection of 9 inhibitors for the study of PI3K/Akt/mTOR signaling pathway supplied as lyophilized powder

• S2739 – PKI-402
• S1039 – Rapamycin (Sirolimus)
• S1009 – BEZ235 (NVP-BEZ235)
• S1078 – MK-2206 dihydrochloride
• S1263 – CHIR-99021 (CT99021)
• S2638 – NU7441 (KU-57788)
• S1092 – KU-55933
• S1275 – BX-912
• S1558 – AT7867

References

1. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010;28(6):1075-1083.
2. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009;8(8):627-644.
3. Fan QW, Knight ZA, Goldenberg DD, Yu W, Mostov KE, Stokoe D, Shokat KM, Weiss WA. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 2006;9(5):341-349.
4. I. W. Flinn JCB, R. R. Furman, J. R. Brown, T. S. Lin, C. Bello, N. A. Giese, A. S. Yu. Preliminary evidence of clinical activity in a phase I study of CAL-101, a selective inhibitor of the p1108 isoform of phosphatidylinositol 3-kinase (P13K), in patients with select hematologic malignancies. J Clin Oncol 2009;27(15s):3543.
   NCI Clinical Trial website, wwwclinicaltrialsgov.
5. A. W. Tolcher TAY, I. Fearen, A. Taylor, C. Carpenter, A. T. Brunetto, M. Beeram, K. Papadopoulos, L. Yan, J. de Bono. A phase I study of MK-2206, an oral potent allosteric Akt inhibitor (Akti), in patients (pts) with advanced solid tumor (ST). J Clin Oncol 2009;27(15):3503.
6. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006;5(8):671-688.
7. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007;12(1):9-22.