Delving into the Latest Updates on Tamibarotene with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Retinobenzoic acid, Tamibaro, Tamibarotene (JAN/INN)

+ [18]

Target

RARα

Action

agonists

Mechanism

RARα agonists(Retinoic acid receptor alpha agonists)

Therapeutic Areas

NeoplasmsHemic and Lymphatic DiseasesOther Diseases+ [2]

Active Indication

Acute Promyelocytic LeukemiaPolycystic Kidney, Autosomal DominantAcute Myeloid Leukemia

Inactive Indication

Advanced Hepatocellular CarcinomaAdvanced Lung Non-Small Cell CarcinomaBreast Cancer+ [9]

Originator Organization

Nippon Shinyaku Co., Ltd.

Active Organization

Syros Pharmaceuticals, Inc.

Rege Nephro Co. Ltd.StartupToko Pharmaceutical Industrial Co. Ltd.

Inactive Organization

LadRx Corp.R&R, Inc.

Zeria Pharmaceutical Co., Ltd.

Drug Highest PhaseApproved

First Approval Date

Japan (11 Apr 2005),

Acute Promyelocytic Leukemia

RegulationFast Track (United States), Orphan Drug (United States), Orphan Drug (European Union)

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Structure/Sequence

Molecular FormulaC22H25NO3

InChIKeyMUTNCGKQJGXKEM-UHFFFAOYSA-N

CAS Registry94497-51-5

The aberrant activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome has been implicated in the exacerbation of myocardial damage and the subsequent development of heart failure following myocardial infarction (MI). Inhibiting NLRP3 inflammasome activation offers a promising therapeutic strategy for mitigating MI-related injury, although no NLRP3 inhibitors have received Food and Drug administration (FDA) approval to date. To identify novel NLRP3 inflammasome inhibitors through the repurposing of FDA-approved drugs, Tamibarotene emerged as a potent inhibitor with a favorable safety profile. Mechanistically, Tamibarotene inhibits NLRP3 inflammasome activation independently of retinoic acid receptor activation, binding to Phe410 and Ile417 within the nucleotide-binding and oligomerization (NACHT) domain in an ATPase activity-dependent manner. This interaction further inhibits the assembly of the NLRP3 inflammasome. In a murine model of MI, Tamibarotene significantly reduced myocardial damage and improved cardiac function by inhibiting NLRP3 inflammasome activation. In summary, NLRP3 has been identified as a direct target of Tamibarotene for myocardial repair following MI, indicating that Tamibarotene could serve as a potential precursor for the development of innovative NLRP3 inhibitors.

01 Mar 2025·INTERNATIONAL IMMUNOPHARMACOLOGY

Silica-induced ferroptosis activates retinoic acid signaling in dendritic cells to drive inflammation and fibrosis in silicosis

Article

Author: Zhang, Zongde ; Tan, Jinzhuo ; Feng, Yingna ; Li, Xingjie ; Xiong, Wenyan

Silicosis, a chronic lung disease caused by inhalation of silica (SiO₂) particles from environmental contamination or industrial exposure, is characterized by persistent inflammation and fibrosis. This study elucidates a novel mechanism where SiO₂ exposure triggers ferroptosis, a lipid peroxidation-dependent form of cell death, in dendritic cells (DCs), thereby activating retinoic acid (RA) signaling. The RA response amplifies inflammatory pathways, including cGAS-STING-IFN-I and IL-1β signaling, exacerbating lung inflammation and fibrosis. The study uses murine models to demonstrate that ferroptosis inhibitors, such as ferrostatin-1, mitigate SiO₂-induced inflammation and collagen deposition. Furthermore, systemic administration of the synthetic retinoid AM80 reduces pulmonary damage by modulating immune cell distribution and promoting lymphocyte homing. These findings reveal the interplay between ferroptosis and RA signaling as a pivotal driver of silicosis pathology and suggest therapeutic avenues targeting ferroptosis and RA modulation for disease management.

10 Jan 2025·ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

Development of the Esterase PestE for Amide Bond Synthesis Under Aqueous Conditions: Enzyme Cascades for Converting Waste PET into Tamibarotene

Article

Author: Salcedo‐Sora, Jesus E. ; Goulding, Ellie ; Allan, Faye E. ; Dittman, Drew ; Ward, Lucy C. ; Carnell, Andrew J.

Abstract:

A growing number of hydrolase enzymes show promiscuous acyltransferase activity, even under aqueous conditions. Here we report, for the first time, the ability of Pyrobaculum calidifontis VA1 esterase (PestE) to catalyse the formation of a wide range of amides in buffer, where the acyl donor forms a significant structural component in the amide product. The reactions occur under mild conditions and can achieve conversions up to 97 % in 6 h for formation of N‐benzylfuranamide as the model reaction. We demonstrate PestE's potential in enzyme cascades to make amides from waste PET plastic and the conversion of the terephthalic acid product to tamibarotene, a drug with activity against acute leukemia. Rational mutagenesis led to identification of PestE variants F33L F289A and F33L. F33L F289A increased conversion of N‐benzylfuranamide by 1.2‐fold, and F33L gave a 4‐fold increase in conversion to tamibarotene.

93

News (Medical) associated with Tamibarotene

15 Apr 2025

·www.prnewswire.com

Rege Nephro Acquires Tamibarotene-Related Assets from Syros Pharmaceuticals for U.S. Clinical Trials

KYOTO, Japan, April 15, 2025 /PRNewswire/ -- Rege Nephro Co., Ltd. (Headquarter: Kyoto, Japan; Chief Executive Officer: Akifumi Morinaka) has announced that it has successfully acquired Tamibarotene-related clinical and non-clinical assets from Syros Pharmaceuticals, Inc. (Headquarters: Boston, MA; NASDAQ:SYRS), through a mutual agreement. The acquisition was completed on February 26, 2025. Tamibarotene (RN-014) is a retinoic acid receptor agonist for which Rege Nephro is currently conducting a Phase 2 clinical trial in Japan in autosomal dominant polycystic kidney disease (ADPKD). Rege Nephro expects to initiate clinical trials in the United States, after confirming the efficacy and safety in Japan. Syros Pharmaceuticals has previously carried out a Phase 3 clinical trial of Tamibarotene for indications including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). This acquisition, encompassing their clinical and non-clinical data including human safety study for New Drug Application (NDA), contracts with a contract manufacturing organization (CMO), and Tamibarotene active pharmaceutical ingredient (API) and drug products, is expected to enhance Rege Nephro's capabilities and streamline operations for its clinical trial operations in the United States. About Rege Nephro: Rege Nephro, founded in 2019, is a clinical-stage biotech company leveraging technology based on research of Prof. Kenji Osafune, deputy director of the Center for iPS Cell Research and Application (CiRA), Kyoto University. The company is developing therapeutics and cell therapy for diseases related to the kidneys, liver, and pancreas. For more information, please visit . About RN-014: RN-014 is a therapeutic candidate for autosomal dominant polycystic kidney disease (ADPKD). It is a retinoic acid receptor (RAR) agonist expected to suppress cyst formation and improve renal function. Rege Nephro initiated a Phase 2 clinical trial in December 2023, and enrollment for the second stage has now been completed. To date, no significant safety concerns have arisen and preliminary efficacy has been demonstrated. SOURCE Rege Nephro Co., Ltd. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Phase 2Cell TherapyAcquisitionPhase 3Phase 1

13 Nov 2024

·endpts.com

Syros' shares plummet as blood cancer drug fails again

Syros Pharmaceuticals’ share price nosedived after its last drug candidate flunked a trial in hematological malignancies for the second time in recent months. In a 190-participant Phase 3 trial, the biotech’s tamibarotene plus azacitidine led to a 23.8% complete response rate in people with newly diagnosed higher-risk myelodysplastic syndromes and RARA gene overexpression versus 18.8% for azacitidine plus placebo. The result was not statistically significant with a p-value of 0.2084, according to a Tuesday release . Syros’ share price $SYRS was down 80% premarket Wednesday. The trial failure triggers a default event under the terms of Syros’ secured loan facility with Oxford Finance. The biotech plans to stop the trial, analyze the data and “evaluate the next steps,” CEO Conley Chee said in the release. The study flop comes just three months after an August disappointment for a tamibarotene triplet regimen in a Phase 2 study of newly diagnosed, unfit patients with acute myeloid leukemia and RARA gene overexpression. Tamibarotene is a retinoid acid receptor alpha agonist. “Tamibarotene’s demise brings to an end Syros’ last clinical program,” TD Cowen analysts said in a Wednesday note, adding the company is likely to end all development of the drug. The biotech previously stopped work on two other clinical candidates, SY-2101 and SY-5609, although it said on an earnings call last month it is looking for licensing opportunities for the latter. The company reported $58.3 million in cash and equivalents as of the end of September.

Phase 3Phase 2Clinical Trial Failure

13 Nov 2024

·firstwordpharma.com

Another study failure puts brakes on Syros’ tamibarotene in blood cancers

After flunking a mid-stage study in front-line acute myeloid leukaemia three months back, Syros Pharmaceuticals’ oral retinoic acid receptor alpha (RARα) agonist, tamibarotene, has hit yet another and a potentially terminal roadblock. This time, the investigational therapy in combination with azacitidine failed to meet the primary endpoint of a late-stage study involving patients with newly diagnosed higher-risk myelodysplastic syndrome (HR-MDS) harbouring RARA gene overexpression – triggering a loan default for the company with Oxford Finance LLC.“We are deeply disappointed by this outcome, particularly for the HR-MDS patients who are seeking a new treatment option for this challenging disease,” said CEO Conley Chee, adding that while Syros will terminate the trial, it will continue to review exisiting data and chart out a further course of action.The Phase III SELECT-MDS-1 study assessed the efficacy and safety of tamibarotene plus azacitidine versus placebo plus azacitidine in RARA-overexpressed patients with HR-MDS, the main goal being the complete response (CR) rate in the first 190 participants. Results showed the tamibarotene plus azacitidine arm demonstrated a CR rate of 23.8% in the initial 190 patients, compared with the placebo plus azacitidine arm’s 18.8%, with no statistically significant difference between the groups. Meanwhile, the safety analysis of all enrolled 245 patients showed the tamibarotene combination was generally well-tolerated, with an adverse event profile comparable to previous studies.Facing financial troubles in the wake of failed deals with Incyte and Pfizer in 2023, the company cut 35% of its workforce last October and discontinued most clinical programmes, including SY-2101 for acute promyelocytic leukaemia, to focus on its lead asset, tamibarotene.

Phase 3Clinical ResultFinancial Statement

100 Deals associated with Tamibarotene

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External Link

KEGG	Wiki	ATC	Drug Bank
D01418	Tamibarotene	L01X	DB04942

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Acute Promyelocytic Leukemia	Japan	Toko Pharmaceutical Industrial Co. Ltd.	11 Apr 2005

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hereditary Sensory and Autonomic Neuropathies	Phase 3	United States	Syros Pharmaceuticals, Inc.	08 Feb 2021
Hereditary Sensory and Autonomic Neuropathies	Phase 3	Austria	Syros Pharmaceuticals, Inc.	08 Feb 2021
Hereditary Sensory and Autonomic Neuropathies	Phase 3	Belgium	Syros Pharmaceuticals, Inc.	08 Feb 2021
Hereditary Sensory and Autonomic Neuropathies	Phase 3	Canada	Syros Pharmaceuticals, Inc.	08 Feb 2021
Hereditary Sensory and Autonomic Neuropathies	Phase 3	Czechia	Syros Pharmaceuticals, Inc.	08 Feb 2021
Hereditary Sensory and Autonomic Neuropathies	Phase 3	France	Syros Pharmaceuticals, Inc.	08 Feb 2021
Hereditary Sensory and Autonomic Neuropathies	Phase 3	Germany	Syros Pharmaceuticals, Inc.	08 Feb 2021
Hereditary Sensory and Autonomic Neuropathies	Phase 3	Hungary	Syros Pharmaceuticals, Inc.	08 Feb 2021
Hereditary Sensory and Autonomic Neuropathies	Phase 3	Israel	Syros Pharmaceuticals, Inc.	08 Feb 2021
Hereditary Sensory and Autonomic Neuropathies	Phase 3	Italy	Syros Pharmaceuticals, Inc.	08 Feb 2021

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Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04797780 (SELECT-MDS-1, CTgov)	Phase 3	RARA positive Myelodysplastic Syndrome \| Hereditary Sensory and Autonomic Neuropathies	246	Tamibarotene+Azacitidine (Tamibarotene + Azacitidine)	agibftqnao = nhvfcvgerc oqyitcxfre (xvccuemrwi, izxssfnpfq - qqbarbqikq) View more	-	10 Apr 2025
				Placebo+Azacitidine (Tamibarotene Matched Placebo + Azacitidine)	agibftqnao = pgmvnbpzdy oqyitcxfre (xvccuemrwi, kyahzhlcnk - ktijnwezdx) View more
NCT04905407 (AML-347 SELECT-AML-1 \| SELECT AML-1 \| SELECT-AML-1, CTgov)	Phase 2	RARA positive Acute Myeloid Leukemia	66	Tamibarotene+Venetoclax+Azacitidine (Part 1: Tamibarotene/Venetoclax/Azacitidine)	uekhavxakk = hdvsymzjhn cyxsuztmag (mbswmourut, dhjsiixedp - sltcnroilc) View more	-	24 Feb 2025
				Tamibarotene+Venetoclax+Azacitidine (Part 2: Tamibarotene/Venetoclax/Azacitidine)	spceliejnf = addtbslzge ntcmsposyc (wwlufueqfy, caivqoogfj - ndyazhekmb) View more
NCT02807558 (CTgov)	Phase 2	Acute Myeloid Leukemia \| Myelodysplastic Syndromes	155	Tamibarotene (R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy)	tlmwhpmbwc = ggxybwgvdy cmuvzbiigk (igvpmldihp, vtxbukyujr - jwttymsbdl) View more	-	13 Dec 2024
				Tamibarotene (Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy)	tlmwhpmbwc = rfepoyirfr cmuvzbiigk (igvpmldihp, aqlzmvylbj - njzetasbjw) View more
NCT04797780 (SELECT-MDS-1, Company_Website) Manual	Phase 3	High Risk Myelodysplastic Syndrome	190	Tamibarotene in combination with azacitidine	wdfgowsqqp(piihbvehbz) = rcbeltrbyk lvbhcwzsmw (wbbxonrfvt, 16.7 - 32.2) Not Met	Negative	12 Nov 2024
				Placebo and azacitidine	wdfgowsqqp(piihbvehbz) = zyjktmhvdd lvbhcwzsmw (wbbxonrfvt, 10.1 - 30.5) Not Met
NCT04905407 (AML-347 SELECT-AML-1, SOHO2024)	Phase 2	RARA positive Acute Myeloid Leukemia RARA overexpression	80	Tamibarotene 6 mg PO BID + Venetoclax-Azacitidine	qnpxabqleo(zugsdfitcy) = vopmekaqtm jhktnjgzdb (nzbxgupvep ) View more	Positive	04 Sep 2024
				Venetoclax-Azacitidine	qnpxabqleo(zugsdfitcy) = bdgglanihj jhktnjgzdb (nzbxgupvep ) View more
NCT04905407 (SELECT-AML-1, NEWS) Manual	Phase 2	RARA positive Acute Myeloid Leukemia RARA	19	tamibarotene+venetoclax+azacitidine	tgbuzccmdy(rucsmsabtb) = pmzdyozvbg vqmmogeyky (pdrxxhbfdi ) View more	Positive	07 Dec 2023
				venetoclax+azacitidin	tgbuzccmdy(rucsmsabtb) = zlvrcnriol vqmmogeyky (pdrxxhbfdi ) View more
NCT02807558 (Pubmed)	Phase 2	Acute Myeloid Leukemia	51	Tamibarotene plus azacitidine	tzdhezcefr(hrgerumhvo) = hematologic AEs were comparable to single agent azacitidine, demonstrating that there was no additional myelosuppression when tamibarotene was combined with azacitidine umrwpqwwzh (xeckzdspmb ) View more	-	07 Dec 2022
NCT04905407 (SELECT-AML-1, ASH 12022 \| ASH 22022) Manual	Phase 2	RARA positive Acute Myeloid Leukemia First line RARA	6	Venetoclax+Azacitidine+Tamibarotene	dvbbjybcth(dptorbrchn) = occurring in more than one patient was febrile neutropenia kgaotewmqn (cgfbdiqzuk ) View more	Positive	15 Nov 2022
				Venetoclax+Azacitidine
NCT04905407 (SELECT-AML-1, SOHO2022)	Phase 2	RARA positive Acute Myeloid Leukemia RARA-positive	-	Tamibarotene/venetoclax/azacitidine	sxgofwcane(ovkieyddor) = hssxfuadif mywtawlsgr (iwvtlnycmo )	-	01 Oct 2022
NCT02807558 (ASH 12020 \| ASH 22020) Manual	Phase 2	RARA positive Acute Myeloid Leukemia First line RARA	51	Azacitidine+SY-1425 (RARA+)	xwermkkici(izpgpxzarm) = febrile neutropenia (27%), pyrexia (12%), pneumonia (12%), and sepsis (10%). nuurlwommu (lhxcwecyge ) View more	Positive	05 Nov 2020
				Azacitidine+SY-1425 (RARA-)