Delving into the Latest Updates on Serabelisib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

FTH-001, INK-1117, MLN-1117

+ [2]

Target

PI3Kα

Mechanism

PI3Kα inhibitors(Phosphatidylinositol 3 kinase alpha inhibitors)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal Diseases

Active Indication

Metastatic Triple-Negative Breast CarcinomaAdvanced Malignant Solid Neoplasm

Inactive Indication

Advanced cancerColorectal CancerEndometrial Carcinoma+ [9]

Originator Organization

Takeda Pharmaceutical Co., Ltd.

Active Organization

Takeda Pharmaceutical Co., Ltd.

Faeth Therapeutics, Inc.Startup

Inactive Organization

Petra Pharma Corp.Startup

Millennium Pharmaceuticals, Inc.

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

Structure

Molecular FormulaC19H17N5O3

InChIKeyBLGWHBSBBJNKJO-UHFFFAOYSA-N

CAS Registry1268454-23-4

Liver cancer is a malignant tumor commonly seen in infants and young children. Serabelisib is a novel and effective phosphoinositide-3-kinase (PI3Kα) inhibitor, currently in trials for solid malignancy treatment, such as bladder cancer. However, it is unclear whether serabelisib affects liver cancer.

OBJECTIVES:

To explore the effects of serabelisib on the proliferation, apoptosis, invasion, and metastasis of HepG2 and HuH-6 cells, and elucidate the relevant molecular mechanisms.

MATERIAL AND METHODS:

The HepG2 cells were treated with 2 μM, 4 μM or 8 μM serabelisib, while the 0-μM group was used as a control. A plate clone formation assay was utilized to measure colony formation ability in each group, a 5-ethynyl-2'-deoxyuridine (EdU) assay examined cell proliferation, a Cell Counting Kit-8 (CCK-8) assay assessed cell viability, flow cytometry measured the cell cycle and apoptosis, JC-1 staining determined mitochondrial membrane potential, and transmission electron microscopy evaluated cell morphology. In addition, gene and protein expression levels of apoptosis markers, epithelial-mesenchymal transition (EMT), Gasdermin D (GSDMD), and the PI3K/protein kinase B (AKT) signaling pathway were measured.

RESULTS:

After serabelisib intervention, HepG2 and HuH-6 cells formed fewer colonies, proliferated more slowly, and had reduced viability. The number of HepG2 and HuH-6 cells in the G2 and S phases decreased, apoptosis and the number of apoptotic bodies increased, and mitochondrial membrane potential decreased. Serabelisib treatment also reduced the migration and invasion capacity of the cells. Furthermore, genes and proteins of the PI3K/AKT signaling pathway were downregulated, while those that promote apoptosis and pyroptosis or inhibit EMT were upregulated.

CONCLUSIONS:

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

01 Nov 2023·Gynecologic oncology

A randomized phase 2 study of sapanisertib in combination with paclitaxel versus paclitaxel alone in women with advanced, recurrent, or persistent endometrial cancer

Article

Author: Faller, Douglas V ; Han, Sileny N ; Makker, Vicky ; Jewell, Andrea ; Wenham, Robert M ; Alía, Eva María Guerra ; Sedarati, Farhad ; Vincent, Sylvie ; Raspagliesi, Francesco ; Neuwirth, Rachel ; Krell, Jonathan ; Baurain, Jean-François ; Braicu, Elena Ioana ; Su, Zhenqiang ; Oza, Amit ; Oaknin, Ana ; Scambia, Giovanni ; Colombo, Nicoletta

OBJECTIVE:

This phase 2 study investigated sapanisertib (selective dual inhibitor of mTORC1/2) alone, or in combination with paclitaxel or TAK-117 (a selective small molecule inhibitor of PI3K), versus paclitaxel alone in advanced, recurrent, or persistent endometrial cancer.

METHODS:

Patients with histologic diagnosis of endometrial cancer (1-2 prior regimens) were randomized to 28-day cycles on four treatment arms: 1) weekly paclitaxel 80 mg/m² (days 1, 8, and 15); 2) weekly paclitaxel 80 mg/m² + oral sapanisertib 4 mg on days 2-4, 9-11, 16-18, and 23-25; 3) weekly sapanisertib 30 mg, or 4) sapanisertib 4 mg + TAK-117 200 mg on days 1-3, 8-10, 15-17, and 22-24.

RESULTS:

Of 241 patients randomized, 234 received treatment (paclitaxel, n = 87 [3 ongoing]; paclitaxel+sapanisertib, n = 86 [3 ongoing]; sapanisertib, n = 41; sapanisertib+TAK-117, n = 20). The sapanisertib and sapanisertib+TAK-117 arms were closed to enrollment after futility analyses. After a median follow-up of 14.4 (paclitaxel) versus 17.2 (paclitaxel+sapanisertib) months, median progression-free survival (PFS; primary endpoint) was 3.7 versus 5.6 months (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.58-1.15; p = 0.139); in patients with endometrioid histology (n = 116), median PFS was 3.3 versus 5.7 months (HR 0.66; 95% CI 0.43-1.03). Grade ≥ 3 treatment-emergent adverse event rates were 54.0% with paclitaxel versus 89.5% paclitaxel+sapanisertib.

CONCLUSIONS:

Our findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable.

TRIAL REGISTRATION:

ClinicalTrials.gov number, NCT02725268.

01 Nov 2023·European journal of medicinal chemistry

Design, synthesis and bioevaluation of PI3Kα-selective inhibitors as potential colorectal cancer drugs

Article

Author: Chen, Yuan-Si ; Lei, Li ; Ban, Yu-Juan ; Zheng, Xue-Mei ; Zhang, Ji-Quan ; Tang, Lei ; Wang, Yu-Jie ; Li, Hong-Liang ; Guo, Bing ; Wang, Jian-Ta ; Dong, Yong-Xi

The dysregulation of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin signaling pathway has been implicated in various human cancers, and isoform-selective inhibitors targeting PI3Kα have received significant interest in recent years. In this study, we have designed and synthesized three series of substituted benzoxazole derivatives based on the clinical candidate TAK-117 (8a). A detailed structure-activity relationship (SAR) study has identified the optimal compound 18a bearing a quinoxaline scaffold. Compared to the control 8a, 18a exhibited 4.4-fold more potent inhibitory activity against PI3Kα (IC₅₀: 2.5 vs 11 nM) and better isoform-selective profiles over other PI3Ks. In addition, 18a showed a 1.5-fold more potent antiproliferative effect against HCT-116 cell lines (IC₅₀: 3.79 vs 5.80 μM) and a better selectivity over the normal tissue cells. 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.

2

News (Medical) associated with Serabelisib

30 May 2024

·www.biospace.com

Faeth Therapeutics to Participate in Upcoming Jefferies Investor Conference

Faeth’s CEO to showcase how AI has unlocked metabolism as a new cancer treatment paradigm AUSTIN, Texas--(BUSINESS WIRE)-- Faeth Therapeutics, (Faeth) a clinical-stage biotechnology company, announced today that Anand Parikh, Chief Executive Officer (CEO), will participate in one-on-one investor meetings at the upcoming Jefferies Global Healthcare Conference being held June 4-6 in New York. To schedule a meeting at the conference with Faeth’s CEO, please contact bridie@faeththerapeutics.com. For more information about the conference, please contact your institutional sales representative at Jefferies. Founded by renowned oncology researchers including Drs. Lew Cantley, Siddhartha Mukherjee, and Karen Vousden alongside CEO Anand Parikh, Faeth is focused on developing therapies targeting cancer metabolism. The role of metabolism in cancer proliferation is well established, yet remains a vastly under-exploited area, with very few cancer metabolism therapies in existence today. Faeth’s differentiated approach to targeting cancer metabolism leverages a systemic understanding of cancer metabolism, functional genomics, and computational biology to develop effective, less toxic therapies. Faeth has a robust clinical and preclinical pipeline driven by the company’s MetabOS discovery platform, which leverages AI, machine learning, and curated data sets to identify targets matched to specific tumor genotypes. Faeth's lead program, FTH-001/003, or "PIKTOR," includes serabelisib, a PI3Kɑ inhibitor, and sapanisertib, an mTORC 1/2 inhibitor, which together effectively shut down the PI3K pathway, the most commonly mutated pathway in cancer. PIKTOR, together with paclitaxel, has already shown outstanding results in a Phase 1b trial including endometrial, ovarian, and breast cancers. Faeth's second clinical program features FTH-002, a specially formulated amino acid sachet, which is administered in conjunction with an amino acid-restricted regimen and radio/chemotherapy. About Faeth Therapeutics Faeth Therapeutics is a clinical-stage biotechnology company at the forefront of oncology research with a robust clinical and preclinical pipeline powered by its AI-driven MetabOS discovery platform. Faeth’s lead program, PIKTOR, has shown outstanding clinical results in a Phase 1b trial and is advancing into a Phase 2 trial in endometrial cancer in 2024. For additional information, visit .

Phase 1Phase 2Clinical Result

08 Nov 2023

·www.biospace.com

Faeth Therapeutics to Participate in the Stifel 2023 Healthcare Conference

AUSTIN, Texas--(BUSINESS WIRE)-- Faeth Therapeutics, an oncology company with clinical programs combining therapeutics with metabolic optimization to achieve greater efficacy, today announced that the company will be participating in a company presentation and 1x1 investor meetings at the Stifel 2023 Healthcare Conference, taking place from November 14-15 in New York City. Anand Parikh, J.D., Chief Executive Officer & Co-Founder, Oliver Maddocks, PhD, Head of Research & Co-Founder, and Debbie Chirnomas, MD, Chief Medical Officer, will present a company overview on Wednesday, November 15, at 3:00 pm ET. About Faeth Therapeutics Faeth Therapeutics, headquartered in Austin, TX, is a clinical-stage biotechnology company focused on bringing breakthrough research in metabolic oncology into the clinic. The company leverages its machine-learning platform to develop precision therapies, augmented by a metabolic regimen involving the patient’s diet, to revolutionize the treatment paradigm. Faeth’s lead program combines FTH-001, serabelisib, with FTH-003, sapanisertib, and an insulin suppressing regimen to slow tumor growth by shutting down the PI3K/mTOR pathway. Faeth’s scientific founders include industry leaders Drs. Lew Cantley, Sid Mukherjee, Karen Vousden. For additional information, visit .

100 Deals associated with Serabelisib

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB14935

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 2	-	Petra Pharma Corp.Startup	01 Sep 2020
Breast Cancer	Phase 2	-	Petra Pharma Corp.Startup	01 Sep 2020
Colorectal Cancer	Phase 2	-	Petra Pharma Corp.Startup	01 Sep 2020
Endometrial Carcinoma	Phase 2	-	Petra Pharma Corp.Startup	01 Sep 2020
Head and Neck Neoplasms	Phase 2	-	Petra Pharma Corp.Startup	01 Sep 2020
Lung Cancer	Phase 2	-	Petra Pharma Corp.Startup	01 Sep 2020
Metastatic Triple-Negative Breast Carcinoma	Phase 2	US	Takeda Pharmaceutical Co., Ltd.	18 Jul 2017
Metastatic Clear Cell Renal Cell Carcinoma	Phase 2	US	Millennium Pharmaceuticals, Inc.	30 Jun 2016
Metastatic Clear Cell Renal Cell Carcinoma	Phase 2	CA	Millennium Pharmaceuticals, Inc.	30 Jun 2016
Metastatic Clear Cell Renal Cell Carcinoma	Phase 2	CZ	Millennium Pharmaceuticals, Inc.	30 Jun 2016

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03193853 (CTgov)	Phase 2	Metastatic Triple-Negative Breast Carcinoma	12	Nab Paclitaxel+Cisplatin+Tak-117+Tak-228	mmxofzwbjk(yzazjaafyn) = zducwlpyhz opagmitzkp (vqutttjnyt, nbthxcedms - tgtfrysyed) View more	-	09 May 2023
NCT03154294 (ASCO2021) Manual	Phase 1	Ovarian Cancer \| Endometrial Carcinoma \| Breast Cancer PI3K Mutation \| AKT Mutation \| MTOR Mutation	19	paclitaxel+sapanisertib+serabelisib	plwbhrljkt(lcybdlkrzz) = yboozhqsoq iqdzvbzner (yrpgvgorpb ) View more	Positive	20 May 2021
NCT02724020 (CTgov)	Phase 2	Metastatic Clear Cell Renal Cell Carcinoma	96	everolimus (Arm A: Single-agent Everolimus 10 mg QD)	elxiiswkzu(timcvdcfew) = caoizgcrhw xdwhfzibsh (xovacdnsbg, twepmtrrbb - xjhtcxpgsm) View more	-	21 Feb 2021
				MLN0128 (Arm B: Single-agent MLN0128 30 mg QW)	elxiiswkzu(timcvdcfew) = rlgycosgfg xdwhfzibsh (xovacdnsbg, xxertnxwdn - tqzztppiso) View more
NCT02725268 (CTgov)	Phase 2	Recurrent Endometrial Cancer	241	Paclitaxel (Paclitaxel 80 mg/m^2)	qxepsqwliq(niybcbxvaw) = wsnwckaqup bjrqyceero (apmavvkkfg, mlsvjebhsj - sxynhzxpxw) View more	-	09 Jun 2020
				Paclitaxel+Sapanisertib (Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg)	qxepsqwliq(niybcbxvaw) = exqfilglma bjrqyceero (apmavvkkfg, ygepfbgorc - rscpfihoen) View more
NCT01449370 (ASCO2015)	Phase 1	Advanced Malignant Solid Neoplasm	76	MLN1117 once daily (QD)	dbarysmcri(txfmyrvuyd) = ykymhbnsgu bjmjtalmfr (lrqjmqzttj ) View more	-	20 May 2015
				MLN1117 3 days per week (MWF)	dbarysmcri(txfmyrvuyd) = vvdotwtijc bjmjtalmfr (lrqjmqzttj ) View more