Evolution of PI3Kγ and δ Inhibitors for Inflammatory and Autoimmune Diseases

Abstract

Phosphoinositol 3-kinases (PI3Ks) γ and δ are key enzymes in hematopoietic cells and have been seen as high-value targets for the treatment of diseases with inflammatory and immunomodulatory components since their discovery and the identification of their roles. In this Perspective we review progress in the application of inhibitors of PI3Kγ and δ to inflammatory and immunological conditions over the past 6 years. We consider progress in the understanding of the roles of PI3Kγ and PI3Kδ in immunology and inflammation, the experience from clinical trials where inhibitors have been tested, and what has been learned about the safety of their use. The extensive medicinal chemistry efforts to discover both isoform selective and dual PI3Kγδ inhibitors are analyzed and detailed. Developments in understanding the structural chemistry of the PI3K enzymes and the factors that govern isoform selectivity are discussed. The effects observed with the known inhibitor compounds in animal models are described.

Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor

“…The lipid kinases (PI3Kα, β, γ, and δ are involved in diverse cellular functions such as cell growth, proliferation, differentiation, motility, survival, and trafficking and have been targeted extensively for drug discovery to treat cancer, autoimmune, and inflammatory diseases . These efforts have focused initially on pan‐PI3K inhibitors, and subsequently on isoform‐selective and dual isoform inhibitors .…”

“…Dual inhibitors of PI3Kδ and PI3Kγ are considered high‐value targets both for inflammation/ autoimmunity and oncology . Compelling preclinical biology of PI3Kδ/γ, initially garnered from gene knockout studies and later substantiated through the use of small‐molecule inhibitors, led to significant investments by the pharmaceutical industry in the last two decades reflected in approximately ~220 patent publications (~80% on PI3Kδ inhibitors, ~15% on PI3Kγ inhibitors, and ~5% for dual inhibitors) …”

“…The lipid kinases (PI3Kα, β, γ, and δ are involved in diverse cellular functions such as cell growth, proliferation, differentiation, motility, survival, and trafficking and have been targeted extensively for drug discovery to treat cancer, autoimmune, and inflammatory diseases. [1][2][3][4][5][6][7][8][9] These efforts have focused initially on pan-PI3K inhibitors, and subsequently on isoform-selective and dual isoform inhibitors. 8,[10][11][12][13] Nearly 15 compounds of varying PI3K isoform selectivity have been explored in the clinic culminating in the launch of four drugs to treat different forms of cancers: idelalisib [Zylidig®, a PI3Kδ selective inhibitor], 5 ] duvelisib [Copiktra®, a dual PI3Kδγ inhibitor], 14 alpelsib [Piqray®, a PI3Kα inhibitor], 15 and copanlisib [Aliqopa®,BAY 80-6946, a dual PI3Kδα inhibitor].…”

“…8,9 Compelling preclinical biology of PI3Kδ/γ, initially garnered from gene knockout studies and later substantiated through the use of small-molecule inhibitors, 7,[17][18][19][20][21][22][23][24][25][26] led to significant investments by the pharmaceutical industry in the last two decades reflected in approximately ~220 patent publications (~80% on PI3Kδ inhibitors, ~15% on PI3Kγ inhibitors, and ~5% for dual inhibitors). 9 Duvelisib (also known as IPI-145 13 ) is the only dual PI3Kδ/γ inhibitor approved to treat relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, 14 at a dose of 25 mg, twice-a-day, associated with dual δ/γ inhibition. Duvelisib demonstrated compelling activity in various preclinical models of autoimmunity, including arthritis, 13 however, efficacy could not be demonstrated in rheumatoid arthritis clinical trials 27 in the dose range associated with a predominant PI3Kδ inhibition (0.5-5 mg, twice a day, PO).…”

Characterizing Pharmacokinetic–Pharmacodynamic Relationships and Efficacy of PI3Kδ Inhibitors in Respiratory Models of TH2 and TH1 Inflammation

“…The PI3Kd isoform is primarily expressed in leukocytes and utilizes lipid phosphorylation to regulate signaling pathways responsible for coordinating a broad range of cellular activities, including cell survival, proliferation, differentiation, and trafficking. That said, these drugs have been found to be well tolerated in animals and humans (Perry et al, 2018). PI3Kd also impacts tumor surveillance, and genetic deletion or pharmacologic antagonism has been demonstrated to suppress tumor growth in a broad range of solid tumors in murine syngeneic models (Stark et al, 2015).…”