Chemical Compounds as Inhibitors of Kinase Activity for the Treatment of Cancer and COPD

Patent Application Title:	Chemical Compounds as Inhibitors of Kinase Activity
Patent Application Number:	WO 2017137535 A1	Publication date:	August 17, 2017
Priority Application:	GB 1602527.2	Priority date:	February 12, 2016
Inventors:	Anderson, N. A.; Barton, N. P.; Campos, S. A.; Cannons, E. P.; Cooper, A. W. J.; Down, K. D.; Doyle, K. J.; Hamblin, J. N.; Inglis, G. G. A.; Le Gall, A.; Patel, V. K.; Peace, S.; Sharpe, A.; White, G. V.
Applicant(s):	GlaxoSmithKline Intellectual Property Development Limited.
Disease Area:	Cancer, sperm mobility, kidney disease, multiorgan failure, asthma, COPD, pancreatitis, and so forth	Biological Target:	PI3 Kinase Activity

Summary:	The phosphatidylinositol 3-kinases (PI3Ks) are a unique family of phospholipid kinases that catalyze phosphorylation of phosphatidylinositol and play key roles in regulation of cell proliferation, survival, metabolism, responses to a number stresses including DNA damage, and so forth. In addition, PI3Ks phosphorylate the hydroxyl group at position 3 in the inositol ring to produce phosphatidylinositol 3-phosphate (PIP), phosphatidylinositol (3,4)-bisphosphate (PIP2), and phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PI3Ks are classified based on their structure, substrate preference, function, and distribution into classes I, II, and III. Each class plays some unique role, for example, in vitro, class I PI3Ks phosphorylate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PI4P), and phosphatidylinositol-4–5-bisphosphate (PI(4,5)P2) produce phosphatidylinositol-3-phosphate (PI3P), phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2), and phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3), respectively. Class I PI3Ks are the most targeted as potential for the treatment of immunology disorders and oncology, and they comprise PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ. Furthermore, class I PI3k consists of a p110 catalytic subunit and is further divided into class 1a and class 1b enzymes. Class 1a PI3K is generally activated in response to growth factor-stimulation of receptor tyrosine kinases.
	Pharmacological inhibition of PI3K may provide therapeutic benefits in modulating T-cell mediated inflammatory responses; activated CDC42 kinase (Akt) phosphorylation and PDK1 activity; B cell proliferation and antibody secretion; neutrophil activation, adhesion, and migration; cancer immunotherapy; neuregulin NRG-1 and ErbB4 receptor in the central nervous system; sensitization in painful inflammatory conditions; retroviral and DNA based viruses; fungal aspergillosis; and so forth.
	The compounds of the invention such as in Formula I are inhibitors of kinase activity; in particular, PI3-kinase activity may be useful in the treatment of PI3-kinase disorders, which might be associated with disease processes such as asthma, chronic obstructive pulmonary disease (COPD), polycystic liver disease and nephronophthisis, bacterial infections, viral respiratory infections, allergic diseases, autoimmune diseases, and so forth. An example of a treatment regimen includes daily dose for oral administration from 0.001 to 50 mg per kg of total body weight. Furthermore, compounds of Formula I may also be administered as prodrugs.
Important Compound Classes:
Key Structures:
Biological Assay:	The PI3K homogeneous time-resolved fluorescence (HTRF) assay: The HTRF assays were used to determine binding of compounds and salts to PI3K-alpha/beta/delta/gamma assays. The plates were read on a PerkinElmer Envision, which measured the TR-FRET between the complex formed between glutathione S-transferase (GST)-tagged pleckstrin homology (PH) and biotinylated phosphatidylinositol (3,4,5)-trisphosphate (PIP3). In the presence of test compounds or salts, the complex is disrupted by the competitive action of nonbiotinylated PIP3. The acceptor/donor ratio was calculated and used in data analysis.
Biological Data:	The compounds and salts of examples 1–37 in the PI3K alpha, beta, delta, and/or gamma assay were found to have pIC50 ≥ 5.
Synthesis:	The palladium residues were removed using silicathiol metal scavenger in three consecutive cycles and crystallizations. In addition, a polymorph experiment was carried out by X-ray powder diffraction. The data were acquired on a PANalytical X’Pert Pro power diffractometer.
Claims:	17 Total claims
	12 Composition of matter claims
	5 Method of use claims
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	Yang W.-R.; Zhu F.-W.; Zhang J.-J.; Wang Y.; Zhang J.-H.; Lu C.; Wang X.-Z.. Reprod. Sci. 2017, 24, 57.

The author declares no competing financial interest.