Small Molecule PI3K Inhibition in Oncology: What’s Been Done and What’s to Come?

PI3 kinases are part of the PI3K/Akt/mTOR signaling pathway that is downstream of Receptor Tyrosine Kinases (RTKs), G-protein-coupled receptors (GPCR), and GTPases such as KRAS. Since their identification in the 1980s, and due to their central role in cancer, the therapeutic targeting of the phosphatidylinositol-3-kinase (PI3K), and more generally, the PI3K/Akt/mTOR axis has been an important focus for the pharmaceutical industry. 

Approval History of PI3K Inhibitors

The PI3K family contains four isoforms: α, β, γ, and δ. While the α, β, and γ isoforms are expressed in all cells, PI3Kδ is mainly expressed in immune cells. Several approaches have been used to target this essential pathway, and a significant number of compounds have entered clinical trials with the goal of identifying compounds with a sufficient safety window to benefit patients. PI3K inhibitors can be separated into three main classes: isoform-selective inhibitors, pan-selective inhibitors, and dual PI3K mTOR inhibitors. Over the last two decades, these efforts led to the approval of five PI3K inhibitors, for several cancer indications (Figure 1).

The first compound approved by the FDA was Gilead’s δ-selective inhibitor idelalisib in 2014 for relapsed follicular B-cell non-Hodgkin lymphoma or relapsed small lymphocytic lymphoma. In 2017, Bayer’s highly potent pan-PI3K inhibitor copanlisib was granted accelerated approval for follicular lymphoma; it is currently the only intravenous PI3K inhibitor on the market. The next approval, also for B cell malignancies, was in 2018 for the dual PI3Kδ/γ inhibitor duvelisib, originated by Intellikine, and marketed by Secura Bio, for relapsed chronic lymphocytic leukemia or small lymphocytic lymphoma. In the same year, duvelisib also received accelerated approval for relapsed FL. 

The selective PI3Kα inhibitor alpelisib, from Novartis, is currently the only PI3K inhibitor approved for an indication outside of hematological malignancies. Alpelisib was approved in 2019, in combination with fulvestrant, for the treatment of HER2-negative or PI3KCA-mutated, advanced or metastatic breast cancer, making it the first approval of a PIK-family inhibitor outside of hematological cancers. In 2022, alpelisib was approved for PIK3CA-related overgrowth spectrum (PROS). 

In 2021, the FDA approved umbralisib from TG therapeutics, a PI3Kδ + CK1ε inhibitor, for the treatment of  FL and MZL in combination with ublituximab, an anti-CD20 antibody. Shortly after receiving accelerated approval, TG Therapeutics filed a BLA and sNDA for umbralisib for the treatment of newly diagnosed and relapsed CLL/SLL. However, in 2022, TG Therapeutics voluntarily withdrew umbralisib from the market due to safety concerns

You can download our poster summary of the history of PI3K inhibitor approvals below:

The full minireview below will highlight the history and current status of PI3K inhibitors, including a discussion of the:

  • PI3K Inhibitors Under Close FDA Attention
  • Resistance Mechanisms
  • Next Generation of PI3K Inhibitors
  • What’s Next in PI3K Inhibition?

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About Julien

Profile photo of Julien Lefranc

Julien Lefranc is a Principal Scientist at Merck KGaA in Darmstadt and is a member of the Early Career Advisory Board at ChemMedChem. Julien Lefranc studied chemistry in Marseille and Montpellier. After his master’s degree, Julien moved to the University of Manchester to carry out his PhD with Prof. Jonathan Clayden working on organolithium reactions and in 2012, he moved to Germany for a postdoctoral stay with Prof. Dirk Trauner working on natural products synthesis. In 2014, Julien started his industrial career with Bayer in Berlin where he worked on several oncology projects. In 2020, he was promoted to Senior Scientist in Medicinal Chemistry at the Innovation Campus Berlin. He assumed his current position in 2021.

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