Pyrazolo[1,5-a]pyridines and their use in cancer therapy

Abstract

Phosphoinositide-3-kinases (PI3Ks) are a group of lipid kinases which phosphorylate the 10 3-hydroxyl of phosphoinositides. They are split into three classes (Class I, II and Ill) and play an important role in cellular signalling [Stephens et al., Curr. Opin. Pharmacal. 2005, 5, 357]. The Class I enzymes are further split into Class Ia and lb based on their mechanism of activation; the Class Ia PI3Ks are heterodimeric structures consisting of a catalytic subunit (p11 Oa, p11 013 or p11 0~) in complex with a regulatory p85 subunit, while 15 the class-IB PI3K (p11 Oy) is structurally similar but lacks a reguiatory subunit linking and instead is activated by 13v subunits of heterotrimeric G-proteins [Walker et al,. Moi.Ce/1., 2000, 6, 909]. PI3Ks play a variety of roles in normal tissue physiology [Foukas & Shepherd, Biochem. 20 Soc. Trans., 2004,32, 330; Shepherd,Acta Physiol. Scand,. 2005, 183, 3], with p110a having a specific role in cancer growth, p11 013 in thrombus formation mediated by integrin aul33 [Jackson et al., Nat. Med., 2005, 11, 507], and p11 Oy in inflammation, rheumatoid arthritis [Camps et al., Nat. Med., 2005, 11, 936] and other chronic inflammation states [Barber et al., Nat. Med., 2005, 11, 933]. The PI3K enzymes produce phosphoinositide 25 3,4,5-triphosphate (PIP3) from the corresponding diphosphate (PIP2), thus recruiting AKT (protein kinase B) through its PH domain, to the plasma membrane. Once bound, AKT is phosphorylated and activated by other membrane bound kinases, and is central to a cascade of events that lead to inhibition of apoptosis [Berrie, Exp. Opin. Invest. Drugs, 2001, 10, 1085].