PX-866 Targets the Phosphatidylinositol-3-kinase (PI-3K) Pathway
PX-866 is a small molecule drug that irreversibly inhibits phosphatidylinositol-3-kinase (PI-3K), a family of intracellular signaling molecules that play essential roles in multiple cellular functions. In normal cells the PI-3K pathway is tightly controlled, whereas the inappropriate activation of PI-3K is important in the pathogenesis of multiple human cancers, making it a rational and attractive target for drug development.
There are 3 classes of PI-3K (I, II and III) categorized based on structure and substrate specificity. The class I PI-3Ks are most tightly associated with human disease and are the targets of PX-866. Four class I PI-3K isoforms have been identified: alpha (α), beta (β), delta (δ) and gamma (γ). The α and β PI-3Ks are broadly expressed in human tissues and deregulation of these two PI-3K family members occurs in many solid tumors. The δ and γ PI-3Ks are primarily expressed in cells that comprise the human immune system and the δ PI-3K is important for lymphomas and leukemia tumor cell growth.
In normal cells the class I PI-3Ks are activated by the stimulation of signaling receptors found on the cell surface that respond to soluble growth factors or cell-cell contact. Once activated, class I PI-3K chemically modifies a membrane-associated lipid molecule called phosphatidylinositol 4,5-bisphosphate (PIP2) to form the product phosphatidylinositol 3, 4, 5-trisphosphate (PIP3). PIP3 serves as a "second messenger" that activates downstream targets, including AKT, the principal mediator of PI-3K signal transduction. The activation of AKT triggers the subsequent activation of additional downstream signaling molecules including the mammalian target of rapamycin (mTORC1), as well as other proteins that control cell growth, metabolism, survival, and proliferation.
In non-diseased cells the PI-3K pathway is tightly controlled by a molecule called PTEN, which counteracts the activity of class I PI-3K by converting PIP3 back to PIP2. Many cancers contain mutations that result in the deregulated activation of the PI-3K pathway. These mutations may function by inhibiting the activity of PTEN, or by overcoming PTEN activity through enhancement of PI-3K signaling. This enhancement can occur by mutations within the PI-3K gene that result in increased enzymatic activity, or by changes to the growth factor receptors that are upstream of PI-3K. These receptors include EGFR, cMet, IGF1R and Her2, which have been shown to be important for multiple cancers. The deregulated activation of PI-3K drives multiple biological activities that are critical for cancer cells, including processes that enable tumors to metastasize and invade normal tissues, continue to grow under conditions of low nutrients or low oxygen, and to resist chemotherapy and radiation therapy (Engelman 2009; Liu, Cheng et al. 2009; Sarker, Reid et al. 2009; Ghayad and Cohen 2010).
Preclinical studies have shown that PX-866 is efficacious in numerous mouse xenograft models of human cancers as a single agent and in combination with chemotherapy, radiation and targeted cancer drugs, such as EGFR inhibitors. Oncothyreon is currently evaluating PX-866 in Phase 1 / 2 and Phase 2 clinical studies in solid tumor diseases.
Engelman, J. A. (2009). "Targeting PI3K signaling in cancer: opportunities, challenges and limitations." Nat Rev Cancer 9(8): 550-562.
Ghayad, S. E. and P. A. Cohen (2010). "Inhibitors of the PI3K/Act/motor pathway: new hope for breast cancer patients." Recent Pat Anticancer Drug Discov 5(1): 29-57.
Liu, P., H. Cheng, et al. (2009). "Targeting the phosphoinositide 3-kinase pathway in cancer." Nat Rev Drug Discov 8(8): 627-644.
Sarker, D., A. H. Reid, et al. (2009). "Targeting the PI3K/AKT pathway for the treatment of prostate cancer." Clin Cancer Res 15(15): 4799-4805.
PX-866 Mechanism of Action
PX-866 is derived from wortmannin, a natural product isolated from Penicillium wortmannin (Wipf, Minion et al. 2004) that is a potent and irreversible inhibitor of PI-3K. Like wortmannin, PX-866 functions as an irreversible inhibitor of PI-3K by forming a covalent bond with the PI-3K molecule. PX-866 has several improvements over wortmannin, including increased stability, reduced toxicity and increased biological activity. In humans and preclinical models, PX-866 is metabolized to produce an active metabolite, 17-OH, that is a more potent PI-3K inhibitor than the parent drug and retains the same irreversible mechanism of action.
Mechanism of Irreversible Inhibition of PI-3K by PX-866
Wipf, P., D. J. Minion, et al. (2004). "Synthesis and biological evaluation of synthetic viridins derived from C(20)-heteroalkylation of the steroidal PI-3-kinase inhibitor wortmannin." Org Biomol Chem 2(13): 1911-1920.
In biochemical assays, PX-866 and the 17-OH metabolite inhibit all four PI-3K family members and have the greatest potency for PI-3K α and β, the two family members that are most strongly linked to solid tumors such as breast, colon, ovarian, and prostate cancers. PX-866 treatment inhibits cell proliferation and decreases the activation of key mediators of cell growth and survival signaling, which improves the activity of chemotherapeutics and radiation when used in combination with PX-866 (Ihle, Williams et al. 2004). In mouse tumor models, PX-866 is extremely potent (2 to 4 mg/kg) when delivered orally and results in sustained inhibition of the PI-3K pathway, a property that is attributable to its unique, irreversible mechanism of action. PX-866 is the only pan-isoform, irreversible PI-3K inhibitor in clinical development. Irreversible inhibition of PI-3K may impart beneficial pharmaceutical properties, including improved potency, fewer side effects and reduced emergence of drug resistance.
PX-866 and Idiopathic Pulmonary Fibrosis
In addition to its role in cancer biology, increased or inappropriate activation of the PI-3K pathway may also play a key role in the underlying pathophysiology of idiopathic pulmonary fibrosis (IPF), an irreversible, progressive lung disease of unknown etiology that represents an area of significant unmet medical need. Emerging data indicate that diseased lung tissue isolated from patients with IPF has reduced PTEN expression and increased PI-3K signaling. Recently published preclinical data demonstrate PX-866 is efficacious in a mouse model of pulmonary fibrosis (Le Cras, Korfhagen et al. 2010). In this model, treatment of mice with PX-866 blocked PI-3K activation in mouse lungs, prevented progressive lung fibrosis and increased lung compliance. These results, taken together with the association of PI-3K with IPF, suggest that PX-866 may be an attractive treatment for this disease.
Le Cras, T. D., T. R. Korfhagen, et al. (2010). "Inhibition of PI3K by PX-866 prevents transforming growth factor-alpha-induced pulmonary fibrosis." Am J Pathol 176(2): 679-686.
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