Clinical review considerations of class I PI3K inhibitors in hematolymphatic malignancies by Center for Drug Evaluation

Several phosphoinositide 3-kinase(PI3 K) inhibitors are currently approved to treat hematolymphatic malignant diseases worldwide, and many drugs that have the same target are in the clinical research stage. In March 2022,duvelisib became the first PI3 K inhibitor approved in China indicated for the treatment of hematolymphatic malignant diseases. Meanwhile, linperlisib and copanlisib have almost completed the technical review of the clinical specialty. The Center for Drug Evaluation(CDE) of the China National Medical Products Administration(NMPA) found that class I PI3 K inhibitors can cause various degrees of immune-related adverse events, which are associated with action mechanisms, affecting the benefit-risk assessment of the drugs. On April 21, 2021, the United States Food and Drug Administration(FDA) convened the Oncologic Drugs Advisory Committee(ODAC)meeting to discuss the safety of PI3 K inhibitors indicated for hematolymphatic malignancies and their related risk of death. The hematological tumor group of CDE of the China NMPA summarized and combined the data on PI3 K inhibitors listed or under technical review for marketing authorization applications and found that such products may have unique efficacy and safety characteristics in Chinese patients with malignant lymphoma.

Overexpressed Cyclin D1 and CDK4 proteins are responsible for the resistance to CDK4/6 inhibitor in breast cancer that can be reversed by PI3K/mTOR inhibitors

CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2-breast cancer patients.Nevertheless,the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance are of great interest.Here,we show that the palbociclibresistant breast cancer cells expressed significantly higher levels of Cyclin D1 and CDK4 proteins because of upregulated protein synthesis.Silencing Cyclin D1 or CDK4 led to cell cycle arrest while silencing Cyclin E1 or CDK2 restored the sensitivity to palbociclib.Furthermore,PI3K/mTOR pathway was hyper-activated in palbociclib-resistant cells,leading to more phosphorylated 4E-BP1 and higher levels of Cyclin D1 and CDK4 translation.Targeting PI3K/mTOR pathway with a specific PI3Kαinhibitor(BYL719)or an mTOR inhibitor(everolimus)reduced the protein levels of Cyclin D1 and CDK4,and restored the sensitivity to palbociclib.The tumor samples expressed significantly higher levels of Cyclin D1,CDK4,p-AKT and p-4E-BP1 after progression on palbociclib treatment.In conclusion,our findings suggest that overexpressed Cyclin D1 and CDK4 proteins lead to the resistance to CDK4/6 inhibitor and PI3K/mTOR inhibitors are able to restore the sensitivity to CDK4/6 inhibitors,which provides the biomarker and rationale for the combinational use of CDK4/6 inhibitors and PI3K/mTOR inhibitors after CDK4/6 inhibitor resistance in breast cancer.

Expert consensus on the clinical application of PI3K/AKT/mTOR inhibitors in the treatment of advanced breast cancer

Phosphoinositide 3‐kinase(PI3K)/protein kinase B(PKB or AKT)/mammalian target of rapamycin(mTOR)signaling pathway(PAM pathway)plays an important role in the development of breast cancer and are closely associated with the resistance to endocrine therapy in advanced breast cancer.Therefore,anticancer treatment targeting key molecules in this signaling pathway has become a research hotspot in recent years.Randomized clinical trials have demonstrated that PI3K/AKT/mTOR inhibitors bring significant clinical benefit to patients with advanced breast cancer,especially to those with hormone receptor(HR)‐positive,human epidermal growth factor receptor(HER)2‐negative advanced breast cancer.Alpelisib,a PI3K inhibitor,and everolimus,an mTOR inhibitor,have been approved by FDA.Based on their high efficacy and relatively good safety profile,an expanded indication of everolimus in breast cancer has been approved by National Medical Products Administration(NMPA).Alpelisib is expected to be approved in China in the near future.The members of the consensus expert panel reached this consensus to comprehensively define the role of PI3K/AKT/mTOR signaling pathway in breast cancer,efficacy and clinical applications of PI3K/AKT/mTOR inhibitors,management of adverse reactions,and PIK3CA mutation detection,to promote the understanding of PI3K/AKT/mTOR inhibitors for Chinese oncologists,improve clinical decision‐making,and prolong the survival of target patient population.

3D-QSAR,Molecular Docking and Molecular Dynamics Simulations of 3-Phenylsulfonylaminopyridine Derivatives as Novel PI3Kα Inhibitors

The p110α,catalytic subunit of PI3Ka,was the primary phosphoinositide 3-kinases(PI3Ks)isoform involved in oncogenic RTK signaling and tumorigenesis.In this study,the three-dimensional quantitative structure-activity relationship(3D-QSAR),molecular docking and molecular dynamics simulation were employed to study the binding mode between 3-phenylsulfonylaminopyridine derivatives and PI3Kα.The stable and reliable 3D-QSAR models were constructed based on the application of the comparative molecular field analysis(CoMFA)model(q^(2)=0.704,r^(2)=0.994)and comparative molecular similarity index analysis(CoMSIA)model(q^(2)=0.804,r^(2)=0.996).The contour maps illustrated relationship between structure and biological activity.The conformation obtained after MD simulation was more stable than the docked conformation.MD simulation was performed in a more realistic environment,and was much closer to physiological conditions.As a result,five novel PI3Kα inhibitors were designed with better biological activity than the template compound 8.

Synthesis and Biological Activity of Imidazo[4,5-c]quinoline Derivatives as PI3K/mTOR Inhibitors

A series of mtidazo[4,5-c]qumoline derivatives（12a-12m） was synthesized with 2-amino-5-bromoben- zoic acid and 4-nitrophenylacetonitrile as starting materials, 6-bromo-4-chloro-3-nitroquinoline as intermediate and Suzuki reaction and closure of the imidazolinone ring with triphosgene as key steps. The structures of the key intermediate and target compounds were confirmed by means of 1H NMR, 13C NMR and HRMS. These compounds show an interesting kinase profile as dual PI3K/mTOR tool compounds.

Synthesis and biological evaluation of 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine derivatives as novel PI3Kδ inhibitors

An efficient synthesis of novel 3-（piperidin-4-yl）isoxazolo[4,5-d]pyrimidine scaffold has been designed and deveopled. A series of 5-phenylurea derivatives was synthesized using this method. Their cytotoxic activities against breast cancer cell line BT-474 were evaluated by CCK-8 assay. Most of them showed potent anti-proliferative activities, of which compound 20 and 21 exhibited IC50 s of 1.565 mmol/L and1.311 mmol/L, respectively. Furthermore, compound 20 and 21 also showed potent inhibitory activities against PI3 Kd with IC50 s of 0.286 mmol/L and 0.452 mmol/L, respectively. These results indicate that these 3-（piperidin-4-yl）isoxazolo[4,5-d]pyrimidine derivatives are novel antitumor agents through the inhibition of PI3 Kd.

Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy

The phosphatidylinositol 3-kinase(PI3K) pathway is frequently activated in human cancers.Class I PI3 Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate(PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate(PIP3), which in turn activates Akt and the downstream effectors like mammalian target of rapamycin(m TOR) to play key roles in carcinogenesis. Therefore, PI3 K has become an important anticancer drug target, and currently there is very high interest in the pharmaceutical development of PI3 K inhibitors. Idelalisib has been approved in USA and Europe as the first-in-class PI3 K inhibitor for cancer therapy. Dozens of other PI3 K inhibitors including BKM120 and ZSTK474 are being evaluated in clinical trials. Multifaceted studies on these PI3 K inhibitors are being performed, such as single and combinational efficacy, resistance, biomarkers,etc. This review provides an introduction to PI3 K and summarizes key advances in the development of PI3 K inhibitors.

A novel PI3K inhibitor XH30 suppresses orthotopic glioblastoma and brain metastasis in mice models

Glioblastoma is carcinogenesis of glial cells in central nervous system and has the highest incidence among primary brain tumors.Brain metastasis,such as breast cancer and lung cancer,also leads to high mortality.The available medicines are limited due to blood-brain barrier.Abnormal activation of phosphatidylinositol 3-kinases(PI3 K)signaling pathway is prevalent in glioblastoma and metastatic tumors.Here,we characterized a 2-amino-4-methylquinazoline derivative XH30 as a potent PI3 K inhibitor with excellent anti-tumor activity against human glioblastoma.XH30 significantly repressed the proliferation of various brain cancer cells and decreased the phosphorylation of key proteins of PI3 K signaling pathway,induced cell cycle arrest in G1 phase as well.Additionally,XH30 inhibited the migration of glioma cells and blocked the activation of PI3 K pathway by interleukin-17 A(IL-17 A),which increased the migration of U87 MG.Oral administration of XH30 significantly suppressed the tumor growth in both subcutaneous and orthotopic tumor models.XH30 also repressed tumor growth in brain metastasis models of lung cancers.Moreover,XH30 reduced IL-17 A and its receptor IL-17 RA in vivo.These results indicate that XH30 might be a potential therapeutic drug candidate for glioblastoma migration and brain metastasis.

Moving towards the chemo-free treatment of lymphoma:hype or reality?

A new generation of novel,effective targeted drugs and cellular therapies include monoclonal antibodies directed at the cell surface,such as the anti-CD-19 tafasitamab which,combined with lenalidomide,is the first therapy approved by the Food and Drug Administration for second-line treatment of diffuse large B-cell lymphoma.Other agents interfere with pro-survival intracellular signaling pathways including drugs that inhibit Bruton tyrosine kinase,phosphatidylinositol-3 kinase(PI3-kinase),and bcl-2.An increasing number of therapies impact the microenvironment,notably checkpoint inhibitors and bispecific antibodies.Chimeric antigen receptor-T cell therapy has improved the outcome of patients with a variety of histologies of lymphoma.Whereas in the past,such therapies would be used inrelapsed and refractory settings,they are now being evaluated as initial treatment in selected patients.With an improved ability to individualize treatment approaches,chemo-free will be a reality for lymphoma patients.