Pipeline

S*BIO has created more than 500 novel compounds as part of its research efforts in developing both mTOR/PI3K dual inhibitors and selective mTOR inhibitors. The programmes are both in advanced lead optimization stage.

The PI3K/Akt signalling pathway. Mitogens acting through receptor tyrosine kinases activate phosphatidyl-3-OH kinase (PI3K) which then activates a series of downstream effectors. One effector critical to cell growth is the mTOR (mammalian target of rapamycin) kinase. In addition, mTOR activity is also controlled by the availability of nutrients (glucose, amino acids and oxygen).

The role of the PI3K/AKT pathway in oncogenesis has been extensively investigated and mutations or altered expression of most of the pathway’s components have been widely implicated in many cancers (amplification of p110 and AKT, activating mutations in p85, loss-of-function mutations in the PTEN gene, mutations of TSC1 and 2). mTOR is also one of the main downstream effectors in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is critically involved in the mediation of cell survival and is a major signaling component downstream of growth factor receptor tyrosine kinases (RTKs). The PI3K-Akt signaling pathway regulates many normal cellular processes including cell proliferation, survival, growth, and motility—processes that are critical for tumorigenesis.

mTOR presents an attractive anti-cancer target with therapeutic potential particularly in cancer cells which are “dependent/addicted” to elevated PI3K signaling.

Several non-tyrosine kinase mTOR inhibitors have been tested in clinical trials: the prototype rapamycin and three rapamycin derivatives, CCI-779 (temsirolimus), RAD001 (everolimus) and AP23573. These studies provide ‘proof of principle’ that mTOR inhibitors can improve cancer patient survival. However, rapamycin and its analogues have not shown broad anti-tumor activity as single agents in early clinical trials.

Small molecules that directly inhibit mTOR kinase (inhibiting both mTORC1 and mTORC2) might be an even more attractive therapeutic approach. Theoretically, direct mTOR kinase inhibitors will block the growth, proliferation and survival effects that are associated with AKT activation via the mTORC2 pathway. This pathway is not inhibited by the rapalogues and may be the reason for their limited single agent activity.

Mammalian target of rapamycin (mTOR) is a PI3K-like serine/threonine kinase that links mitogenic stimuli and nutrient status to cell growth, cell proliferation, cell survival, cell motility, protein synthesis and gene transcription. Growth factors and nutrients regulate mTOR, the catalytic subunit of two distinct complexes:

• Activation of the rapamycin- and nutrient sensitive multiprotein complex mTORC1 (containing the accessory protein RAPTOR (regulatory-associated protein of mTOR), mLST8 (also known as GßL) and PRAS40 (proline-rich AKT substrate 40kDa) results in phosphorylation of 4E-binding protein 1 and ribosomal p70 S6 kinase and thereby regulating mRNA transcription.
• The second complex mTORC2 is growth-factor–sensitive and rapamycin- and nutrient-insensitive and involves RICTOR (rapamycin-insensitive companion of mTOR), mLST8, mSIN1 and PROTOR (protein abserved with RICTOR). mTORC2 directly phosphorylates AKT/PKB at S473 which is necessary for the full activation of AKT.

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