Delving into the Latest Updates on Serabelisib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

6-(2-Aminobenzo[d]oxazol-5-yl)imidazo [1,2-a]pyridine-3-yl morpholinomethanone, MLN1117

+ [5]

Target

PI3Kα

Mechanism

PI3Kα inhibitors(Phosphatidylinositol 3 kinase alpha inhibitors)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesUrogenital Diseases+ [1]

Active Indication

Recurrent Endometrial CancerMetastatic Triple-Negative Breast CarcinomaAdvanced Malignant Solid Neoplasm+ [2]

Inactive Indication

Advanced cancerColorectal CancerHead and Neck Neoplasms+ [8]

Originator Organization

Takeda Pharmaceutical Co., Ltd.

Active Organization

University HospitalTakeda Pharmaceuticals International, Inc.

Takeda Pharmaceutical Co., Ltd.

+ [3]

Inactive Organization

Millennium Pharmaceuticals, Inc.

Petra Pharma Corp.Startup

Drug Highest PhasePhase 2

First Approval Date-

RegulationOrphan Drug (US)

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Structure/Sequence

Molecular FormulaC19H17N5O3

InChIKeyBLGWHBSBBJNKJO-UHFFFAOYSA-N

CAS Registry1268454-23-4

FadD32, a fatty acyl-AMP ligase, plays an indispensable role in mycobacterial mycolic acid synthesis and is a validated target for tuberculosis (TB) drug development. The crystal structure of Mycobacterium tuberculosis (Mtb)FadD32 has laid the foundation of structure-based drug discovery against this crucial enzyme. Here, we screened the "isoxazole" scaffold containing molecules against MtbFadD32 and identified a compound 2,4-dibromo-6-[3-(trifluoromethyl)-1,2-oxazol-5-yl]phenol (M1) with specific inhibitory activity against Mtb. Kinetics experiments showed that M1 inhibits MtbFadD32 and MtbFadD28 activity. The transcriptomics response of Mtb disclosed M1-mediated regulation of mycobacterial decisive genes involved in cell wall synthesis, consequently creating unfavorable conditions for Mtb survival. Further, M1 curtails the Mtb survival in infected macrophages and reduces Mtb burden and tubercular granulomas in a chronic infection model of BALB/c mice. Our findings provide an effective chemical scaffold to inhibit MtbFadD32 with the potential to inhibit multiple MtbFadD family of enzymes for further development as a promising candidate for treating TB.

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

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

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
Recurrent Endometrial Cancer	Phase 2	NL	Millennium Pharmaceuticals, Inc.	01 Apr 2016
Recurrent Endometrial Cancer	Phase 2	US	Millennium Pharmaceuticals, Inc.	01 Apr 2016
Recurrent Endometrial Cancer	Phase 2	IT	Millennium Pharmaceuticals, Inc.	01 Apr 2016
Recurrent Endometrial Cancer	Phase 2	GB	Millennium Pharmaceuticals, Inc.	01 Apr 2016
Recurrent Endometrial Cancer	Phase 2	BE	Millennium Pharmaceuticals, Inc.	01 Apr 2016
Recurrent Endometrial Cancer	Phase 2	CA	Millennium Pharmaceuticals, Inc.	01 Apr 2016
Recurrent Endometrial Cancer	Phase 2	ES	Millennium Pharmaceuticals, Inc.	01 Apr 2016
metastatic non-small cell lung cancer	Phase 1	US	Millennium Pharmaceuticals, Inc.	03 Jun 2015
metastatic non-small cell lung cancer	Phase 1	NL	Millennium Pharmaceuticals, Inc.	03 Jun 2015
metastatic non-small cell lung cancer	Phase 1	CA	Millennium Pharmaceuticals, Inc.	03 Jun 2015

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03154294 (CTgov)	Phase 1	Advanced Malignant Solid Neoplasm	19	paclitaxel+TAK-117+TAK-228 (Cohort 1)	kvrgiqhern(ueoyqbwhnl) = evffuhfxxr mlasnksdoz (kwxgptubtx, roohqanzqu - kulplhksoe) View more	-	26 Jul 2024
				paclitaxel+TAK-117+TAK-228 (Cohort 2)	kvrgiqhern(ueoyqbwhnl) = finvltivyj mlasnksdoz (kwxgptubtx, xmijjhwqcv - djpwdvlelr) View more
NCT03193853 (CTgov)	Phase 2	Metastatic Triple-Negative Breast Carcinoma	12	Nab Paclitaxel+Cisplatin+Tak-117+Tak-228	(pbcqnnxfsu) = qshmnngbsm mbzmdwjger (lvyvnhzgoq, rgdjxzvvgd - urtnciucmn) View more	-	09 May 2023
NCT03154294 (Pubmed)	Phase 1	Advanced Malignant Solid Neoplasm	19	Sapanisertib 3 or 4 mg + Serabelisib 200 mg + Paclitaxel 80 mg/m2	wukmsofvgk(yvhzhsbccd) = 9% szbglvrtge (xgignkuhmj ) View more	Positive	14 Jul 2022
NCT03154294 (ASCO 12021 \| ASCO 22021) Manual	Phase 1	Ovarian Cancer \| Endometrial Carcinoma \| Breast Cancer PI3K Mutation \| AKT Mutation \| MTOR Mutation	19	paclitaxel+sapanisertib+serabelisib	(zjwfrgpozu) = akgppquntt zsmpufozyw (eysarzoxyj ) 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)	(nmdecujgqw) = kwfcvannzp fcwjwohdtc (obfwptdsfd, tmhvtvrhvv - nhqettkmwe) View more	-	21 Feb 2021
				MLN0128 (Arm B: Single-agent MLN0128 30 mg QW)	(nmdecujgqw) = dnahjgiymb fcwjwohdtc (obfwptdsfd, xakmdplqcc - ejaseaukov) View more
NCT02725268 (phase 2 study of sapanisertib in combination with paclitaxel versus paclitaxel alone in women with advanced, recurrent, or persistent endometrial cancer, CTgov)	Phase 2	Recurrent Endometrial Cancer	241	Paclitaxel (Paclitaxel 80 mg/m^2)	(vgrstzigkb) = wjklueziys ckcvwicekv (qzpfsahjlb, fjwrciwfes - ipavkrxxto) View more	-	09 Jun 2020
				Paclitaxel+Sapanisertib (Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg)	(vgrstzigkb) = mjyojrejek ckcvwicekv (qzpfsahjlb, zrvgsqsqja - pqmlptzlpl) View more
NCT03154294 (ASCO2020)	Phase 1	Ovarian Cancer \| Advanced Endometrial Carcinoma \| Advanced breast cancer	-	Sapanisertib (TAK-228) + Serabelisib (TAK-117) + Paclitaxel	okkcodvxfn(vvcsgadjyk) = One DLT occurred due to renal dysfunction in cohort 5 hackdqbupq (hzxbpjbaqs ) View more	Positive	25 May 2020
NCT01449370 (ASCO2015)	Phase 1	Advanced Malignant Solid Neoplasm	76	MLN1117 once daily (QD)	ppfanthgyo(fskvlbhfos) = ftgrsxchrx efpxlcsjqv (melmlyfscf ) View more	-	20 May 2015
				MLN1117 3 days per week (MWF)	ppfanthgyo(fskvlbhfos) = ipscgmsndg efpxlcsjqv (melmlyfscf ) View more