Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016–2020)

ABSTRACT

Introduction: The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway plays a central role in regulating cell growth and proliferation and thus has been considered as effective anticancer drug targets. Many PI3K inhibitors have been developed and progressed to various stages of clinical trials, and some have been approved as anticancer treatment. In this review, we discuss the drug design and clinical development of PI3K inhibitors over the past 4 years. We review the selectivity and potency of 47 PI3K inhibitors. Structural determinants for increasing selectivity toward PI3K subtype-selectivity or mutant selectivity are discussed. Future research direction and current clinical development in combination therapy of inhibitors involved in PI3Ks are also discussed.

Area covered: This review covers clinical trial reports and patent literature on PI3K inhibitors and their selectivity published between 2016 and 2020.

Expert opinion: To PI3Kα mutants (E542K, E545K, and H1047R), it is highly desirable to design and develop mutant-specific PI3K inhibitors. It is also necessary to develop subtype-selective PI3Kα inhibitors to minimize toxicity. To reduce drug resistance and to improve efficacy, future studies should include combination therapy of PI3K inhibitors with existing anticancer drugs from different pathways.

KEYWORDS:

• PI3K
• cancer
• inhibitors
• clinical trials
• trafficking cascade
• combination therapy

Article highlights

• PI3K/mTOR inhibitors have shown great promise in cancer treatment. Seven drugs have been approved by the US FDA.

• Selective inhibitors have been developed for subtype-specific inhibition against PI3Kα, β, γ, and δ.

• New therapeutic uses of PI3K inhibitors are actively investigated in clinical trials.

• The synergy effect of PI3K inhibitors and anticancer drugs from other pathways shows improved efficacy in different cancers.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are the founders and shareholders of Kither Biotech, a company producing PI3K inhibitors. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

DAS likes to acknowledge the financial support sponsored by the Scientific Research Support Fund of the Ministry of Higher Education & Scientific Research and the Deanship of Scientific Research and Graduate Studies at Al-Zaytoonah University of Jordan (Grant number: MPH/1/8/2017).