Class I phosphatidylinositide-3-kinases (PI3Ks) are lipid kinases that catalyze the phosphorylation of phosphoinositide-4,5-bisphosphate (PIP2) at the 3-position of the inositol to generate the important second messenger phosphoinositide-3,4,5-trisphosphate (PIP3). Class I PI3Ks are further divided into two subclasses IA and IB. Subclass IA members include PI3Kα, PI3Kβ and PI3Kδ. PI3Kδ (p110δ) is mainly expressed in circulating leukocytes and lymphoid tissues. Its critical roles in B-cells are well documented (Puri and Gold, 2012). PI3Kδ is the central signaling enzyme that mediates the effects of multiple receptors on B cells. Upon antigen binding to B cell receptor (BCR), PI3Kd can be activated through THE LYN and Syk signaling cascade. PI3Kδ not only mediates the signals from antigen via BCR, but also transduces the signals from multiple stimuli through different receptors on B cells. The CD40 ligand (CD40L) from T cells, cytokines and chemokines from stromal cells, and endotoxin from bacteria etc. can trigger PI3Kδ activation in B cells.
PI3Kd plays important roles in B cells activation, development, survival and migration under physiological condition.
There is now mounting evidence supporting the importance of PI3K signaling in B-cell malignancies. Constitutive activation of the PI3K pathway was detected in several DLBCL (Diffuse large B-cell lymphoma)/ MCL (Mantle cell lymphoma) cell lines and primary cells from DLBCL/MCL patients (Uddin et al., 2006; Rudelius et al., 2006). PI3K activation has also been observed in follicular lymphoma (FL), mediastinal DLBCL, and Hodgkin’s lymphoma (Renne et al., 2007; Garcia-Martinez et al., 2011). Herman et al. (2010) reported significantly higher PI3K activity in primary cells from patients with CLL than that in normal hematopoietic cells.
We have designed HMPL-689 with superior PI3K isoform selectivity, in particular to spare PI3Kɣ (gamma) to minimise the serious infection observed with duvelisib due to its strong immune suppression. HMPL-689 potency, particularly at the whole blood level allows for reduced daily doses to minimise compound related toxicity such as the high level of liver toxicity observed with the idelalisib 150mg twice-daily dose regime. HMPL-689’s pharmacokinetic properties have been found to be favourable with expected good oral absorption, moderate tissue distribution and low clearance, suitable for once daily dosing. It is also expected that HMPL-689 will have low risk of drug accumulation and drug/drug interaction due to Cytochrome P450 (CYP) inhibition/induction.
Given the above, we believe that HMPL-689 has the potential to be a best-in-class PI3Kδ agent, superior to both idelalisib and duvelisib, and HMP intends to pursue global development.