Development of PI3K inhibitors: Advances in clinical trials and new strategies (Review)

Abstract
Phosphatidylinositol 3-kinases (PI3Ks) are an essential family of lipid kinases found throughout mammalian cells, playing pivotal roles in fundamental cellular processes such as growth, survival, metabolism, and migration. The PI3K family comprises several isoforms, including Class I, Class II, and Class III PI3Ks, with Class I PI3Ks being particularly involved in regulating the PI3K/AKT/mTOR signaling pathway. When this pathway is overactivated, it contributes to tumorigenesis by driving processes like cell proliferation, survival, and metastasis. Alterations in PI3Ks, such as overexpression or mutations—especially in the PIK3CA gene—are frequently associated with a variety of cancers, including breast cancer, colorectal cancer, and glioblastomas. This makes PI3Ks crucial players in cancer progression, thereby making them attractive targets for cancer therapy.

The hyperactivation of the PI3K/AKT/mTOR signaling pathway is a defining characteristic of many cancers, and inhibiting PI3K activity has emerged as a promising approach for cancer treatment. A range of PI3K inhibitors has been developed and tested in clinical trials, yielding positive results in reducing tumor growth and improving patient prognosis. These inhibitors function by directly targeting the PI3K enzyme or by decreasing its expression, thus preventing the activation of downstream signaling that drives unchecked cell division and survival. Among the PI3K inhibitors that have shown clinical efficacy, Idelalisib, Alpelisib, and Duvelisib have received FDA approval. Idelalisib is used to treat refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), while Alpelisib has been approved for ER+/HER2- advanced metastatic breast cancer, often in combination with other therapies. Duvelisib, a dual inhibitor targeting both PI3K-δ and PI3K-γ, has demonstrated promising results in the treatment of hematologic cancers.

This review highlights the most recent advancements in PI3K inhibitors, categorizing them into three major classes based on their specificity and mode of action: Pan-PI3K inhibitors, isoform-specific PI3K inhibitors, and dual PI3K/mTOR inhibitors. Pan-PI3K inhibitors target all PI3K isoforms, while isoform-specific inhibitors focus on one or a few specific isoforms, offering a more targeted approach. Dual PI3K/mTOR inhibitors simultaneously block both PI3K and mTOR, which are often co-activated in cancer cells, allowing for a more complete disruption of the pathway. Understanding the structures of these inhibitors and their corresponding structure-activity relationships (SAR) is crucial for evaluating their effectiveness and for overcoming the challenge of drug resistance. Structural modifications to enhance selectivity, potency, and pharmacokinetic properties have been introduced to improve their clinical performance.

In addition, this review explores the progress of PI3K inhibitors in clinical settings, particularly ongoing trials and efforts to address drug resistance. Resistance to PI3K-targeted therapies remains a major challenge, often limiting the long-term effectiveness of these drugs. To overcome this, new therapeutic strategies are being developed, such as the use of PI3K degradation agents. These agents aim to reduce PI3K levels by promoting the degradation of the PI3K protein, thus potentially overcoming resistance caused by mutations or compensatory signaling pathways. This strategy represents a promising direction for the development of next-generation PI3K inhibitors, which may offer more effective treatment options, particularly for cancers that are resistant to current therapies.

In conclusion, PI3Ks remain a critical target for cancer therapy, with continued research and development of PI3K inhibitors offering hope for improved treatment outcomes. The ongoing exploration of new PI3K inhibition IPI-145 strategies, including isoform-specific inhibitors, dual-target drugs, and PI3K degradation agents, holds the potential to provide more effective therapies for PI3K-driven cancers and to address the persistent challenge of drug resistance.