serabelisib (MLN1117)

P2, N=40, Not yet recruiting, Faeth Therapeutics | N=120 --> 40 | Initiation date: Sep 2024 --> Dec 2024

In our study, we investigated how phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway inhibitors (TAK-228, everolimus and TAK-117) affect PD-L1 expression and function in preclinical bladder cancer cell models. These preclinical findings suggest that mTOR inhibition with TAK-228 can increase PD-L1 levels, potentially impacting the specific immune response against UC cells. This highlights the rationale for exploring the combination of mTOR inhibitors with ICIs in patients with advanced UC.

A series of dual EGFR/PI3Kα inhibitors was synthesized using pharmacophore hybridization of the third-generation EGFR inhibitor olmutinib and the PI3Kα selective inhibitor TAK-117. Compound 30k exhibited a significant antiproliferative effect in NCI-H1975 cells with a higher selectivity profile than olmutinib. The potential antitumor mechanism, molecular binding modes, and in vitro metabolic stability of compound 30k were also clarified.

P1, N=19, Completed, Avera McKennan Hospital & University Health Center | Active, not recruiting --> Completed | N=30 --> 19

P2, N=120, Not yet recruiting, Faeth Therapeutics

P1, N=68, Active, not recruiting, Faeth Therapeutics | Recruiting --> Active, not recruiting | Phase classification: P1b --> P1

In this study, we have designed and synthesized three series of substituted benzoxazole derivatives based on the clinical candidate TAK-117 (8a)...The potential antitumor mechanism and in vitro metabolic stability of 18a were also investigated. Notably, pharmacokinetic assays indicated that 18a had a higher plasma exposure, a higher maximum concentration and shorter elimination time compared to 8a.

Priming patients' chemotherapy-pretreated metastatic TNBC with PIKTOR led to very prolonged response/disease control with subsequent cis/nab pac, followed by pembrolizumab, in 3 of 10 treated patients. Our multi-omics approach revealed a higher number of genomic alterations, reductions in MMR, and alterations in immune and stress response pathways post-PIKTOR in patients who had durable responses.

Serabelisib inhibited the PI3K/AKT signaling pathway, thereby inhibiting EMT and promoting apoptosis and pyroptosis in HepG2 and HuH-6 cells.

P2, N=12, Completed, Baylor Research Institute | Active, not recruiting --> Completed

The PI3K inhibitors which are under clinical trial studies include GDC-0032, INK1117 for PI3K-α, and AZD8186 for PI3K-β. This review primarily focuses on the structural insights and structure anticancer activity relationship studies of recent PI3K inhibitors including their clinical stages of development and therapeutic values.

Sapanisertib with or without TAK-117 was less tolerable and did not improve efficacy vs. everolimus in patients with advanced ccRCC who had relapsed after or were refractory to VEGF-targeted therapies. Dual mTORC1/2 inhibition may not be an effective therapeutic approach for these patients.

P1b, N=68, Recruiting, Faeth Therapeutics | Trial completion date: Nov 2023 --> Sep 2024 | Trial primary completion date: Nov 2023 --> Sep 2024

Among these, PI3Kα specific inhibitor alpelisib was approved by FDA for breast cancer and other α-isoform specific inhibitors such as inavolisib and serabelisib reached clinical trials. Moreover, correlated motions of all residues were generally higher for ATP except the H1047R mutation which exhibited a distinguishable reduction. The results presented here could be guiding for pre-clinical and clinical studies of personalized medicine where individual mutations are a strong consideration point.

P2, N=10, Active, not recruiting, Baylor Research Institute | Trial completion date: Jun 2022 --> Dec 2022

P1b, N=58, Recruiting, Faeth Therapeutics

The PI3K inhibitors which are under clinical trial studies include GDC-0032, INK1117 for PI3K-α, and AZD8186 for PI3K-β. This review primarily focuses on the structural insights and structure anticancer activity relationship studies of recent PI3K inhibitors including their clinical stages of development and therapeutic values.

P2, N=96, Completed, Millennium Pharmaceuticals, Inc. | Trial completion date: Mar 2020 --> Oct 2020

P2, N=10, Active, not recruiting, Baylor Research Institute | Recruiting --> Active, not recruiting | N=20 --> 10

P1b/2, N=60, Not yet recruiting, Petra Pharma | Initiation date: Jun 2020 --> Sep 2020

Additional treatment arms of SAP alone (weekly dosing) and SAP+TAK-117 were closed after futility analyses. Median PFS was longer with SAP+PAC vs. PAC in pts with endometrial cancer but did not reach statistical significance. PFS was particularly longer in the endometrioid subtype but again was not significant, and further studies are warranted.