Intellikine is focused on developing small molecule inhibitors of a critical intracellular signaling component known as phosphoinositide-3 kinase (PI3K). The PI3K pathway stimulates numerous processes that promote cell proliferation, growth, motility, metabolism and survival. Inappropriate activation of these processes contributes to the development and progression of immune-mediated inflammatory disorders.
The PI3Kδ/γ isoforms are mainly expressed in cells of the immune system and contributes to innate and adaptive immunity. PI3Kδ/γ regulates diverse immune cell functions, including:
- Suppression of B-cell activation and function (PI3Kδ)
- Suppression of T-lymphocyte proliferation (PI3Kδ)
- T-cell trafficking (PI3Kδ)
- Th1-Th2 differentiation and Treg function (PI3Kδ)
- Inhibition of neutrophil (leukocyte) chemotaxis (PI3Kδ/γ)
- Inhibition of mast cell activation (PI3Kδ/γ)
- Intact macrophage phagocytosis (PI3Kδ/γ)
- Endothelium activation (PI3Kδ/γ)
- Microglial activation (PI3Kγ)
Isoform-specific PI3Kδ/γ inhibitors are expected to have therapeutic effects in these diseases without interfering with general PI3K signaling critical to the normal function of other cellular systems.
Potential indications: Rheumatoid arthritis, multiple sclerosis, systemic lupus erythermatosus (SLE), psoriasis, transplantation, asthma, COPD, allergic diseases.
Achievement: More than 600 compounds comprising several distinct chemical series have been synthesized using medicinal chemistry methods guided by class I PI3K isoforms X-ray crystal structures and molecular modeling. The lead series is synthetically tractable, exhibits potent biochemical inhibition against PI3Kδ/γ, and displays a strong structure-activity relationship. Most importantly, sub-nanomolar biochemical activities translate consistently into inhibition of B/T cell signaling and function at single digit nanomolar concentrations.
Differential selectivity within the PI3K family for the lead series appears to be exquisitely selective with regard to PI3Kδ and PI3Kγand more than two orders of magnitude relative to other PI3K isoforms. The lead series also demonstrates exquisite selectivity (IC50 > 1μM) against a panel of more than 400 protein kinases. We anticipate moving this program into formal IND-enabling preclinical development in the middle of 2009.