Delving into the Latest Updates on VTP-195183 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [4]

Target

RARα

Mechanism

RARα agonists(Retinoic acid receptor alpha agonists)

Therapeutic Areas

NeoplasmsHemic and Lymphatic DiseasesSkin and Musculoskeletal Diseases+ [3]

Active Indication-

Inactive Indication

Acute Promyelocytic LeukemiaBreast CancerChronic Myelomonocytic Leukemia+ [7]

Originator Organization

Allergan Ltd. (Ireland)

Active Organization-

Inactive Organization

Io Therapeutics, Inc.The Sidney Kimmel Comprehensive Cancer CenterAllergan Specialty Therapeutics, Inc.

+ [2]

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC22H22ClF2NO4

InChIKeyPNAWUIKCVQSLFG-UHFFFAOYSA-N

CAS Registry367273-07-2

Activities of the retinoic acid receptor (RAR)α and RARγ are important to hematopoiesis. Here, we have investigated the effects of receptor selective agonists and antagonists on the primitive human hematopoietic cell lines KG1 and NB-4 and purified normal human hematopoietic stem cells (HSCs). Agonizing RARα (by AGN195183) was effective in driving neutrophil differentiation of NB-4 cells and this agonist synergized with a low amount (10 nM) of 1α,25-dihydroxyvitamin D₃ to drive monocyte differentiation of NB-4 and KG1 cells. Treatment of cultures of human HSCs (supplemented with stem cell factor ± interleukin 3) with an antagonist of all RARs (AGN194310) or of RARα (AGN196996) prolonged the lifespan of cultures, up to 55 days, and increased the production of neutrophils and monocytes. Slowing down of cell differentiation was not observed, and instead, hematopoietic stem and progenitor cells had expanded in number. Antagonism of RARγ (by AGN205728) did not affect cultures of HSCs. Studies of CV-1 and LNCaP cells transfected with RAR expression vectors and a reporter vector revealed that RARγ and RARβ are activated by sub-nM all-trans retinoic acid (EC₅₀-0.3 nM): ~50-fold more is required for activation of RARα (EC₅₀-16 nM). These findings further support the notion that the balance of expression and activity of RARα and RARγ are important to hematopoietic stem and progenitor cell expansion and differentiation.

01 Jun 2013·LeukemiaQ1 · MEDICINE

ATRA and the specific RARα agonist, NRX195183, have opposing effects on the clonogenicity of pre-leukemic murine AML1-ETO bone marrow cells

Q1 · MEDICINE

Article

Author: L C Y Chee ; G A McArthur ; L E Purton ; J Hendy

All-trans retinoic acid (ATRA) is used successfully in the treatment of acute promyelocytic leukemia (APL). ATRA enhances hematopoietic stem cell self-renewal through retinoic acid receptor (RAR)γ activation while promoting differentiation of committed myeloid progenitors through RARα activation. Its lack of success in the treatment of non-APL acute myeloid leukemia (AML) may be related to ATRA's non-selectivity for the RARα and RARγ isotypes, and specific RARα activation may be more beneficial in promoting myeloid differentiation. To investigate this hypothesis, the effects of ATRA and the specific RARα agonist NRX195183 was assessed in AML1-ETO (AE)-expressing murine bone marrow (BM) progenitors. ATRA potentiated the in vitro clonogenicity of these cells while NRX195183 had the opposite effect. Morphological and flow cytometric analysis confirmed a predominantly immature myeloid population in the ATRA-treated AE cells while the NRX195183-treated cells demonstrated an increase in the mature myeloid population. Similarly, NRX195183 treatment promoted myeloid differentiation in an AE9a in vivo murine model. In the ATRA-treated AE cells, gene expression analyses revealed functional networks involving SERPINE1 and bone morphogenetic protein 2; AKT phosphorylation was upregulated. Collectively, these findings confirm the contrasting roles of specific RARα and RARγ activation in the clonogenicity and differentiation of AE cells with potential significant implications in the treatment of non-APL AML using a specific RARα agonist.

01 Feb 2010·Journal of Orthopaedic ResearchQ3 · MEDICINE

Inhibition of ectopic bone formation by a selective retinoic acid receptor α‐agonist: A new therapy for heterotopic ossification?

Q3 · MEDICINE

Article

Author: Masahiro Iwamoto ; Tiffany N. Morrison ; Kengo Shimono ; Julie A. Williams ; Wei-en Tung ; Maurizio Pacifici ; Roshantha A. Chandraratna

AbstractHeterotopic ossification (HO) consists of formation of ectopic cartilage followed by endochondral bone and is triggered by major surgeries, large wounds, and other conditions. Current therapies, including low‐dose irradiation, are not always effective and do not target the skeletogenic process directly. Because chondrogenesis requires a decrease of nuclear retinoic acid receptor α (RARα) action, we reasoned that pharmacologic activation of this receptor pathway should inhibit HO. Thus, we selected the synthetic retinoid NRX195183, a potent and highly selective RARα‐agonist, and found that it did inhibit chondrogenesis in mouse limb micromass cultures. We established a mouse HO model consisting of subcutaneous implantation of Matrigel mixed with rhBMP‐2. Control mice receiving daily oral doses of vehicle (peanut oil) or retinol (a natural nonactive retinoid precursor) developed large HO‐like masses by days 9–12 that displayed abundant cartilage, endochondral bone, vessels, and marrow. In contrast, formation of HO‐like masses was markedly reduced in companion mice receiving daily oral doses of α‐agonist. These ectopic masses contained sharply reduced amounts of cartilage and bone, blood vessels, and TRAP‐positive osteoclasts, and expressed markedly lower levels of master chondrogenic genes including Sox9, cartilage genes such as collagen XI and X, and osteogenic genes including Runx2. The data provide proof‐of‐principle evidence that a pharmacological strategy involving a selective RARα‐agonist can indeed counteract an ectopic skeletal‐formation process effectively and efficiently, and could thus represent a novel preventive treatment for HO. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:271–277, 2010

100 Deals associated with VTP-195183

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB05653

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Chronic Myelomonocytic Leukemia	Phase 2	US	Io Therapeutics, Inc.	30 Jan 2017
Chronic Myelomonocytic Leukemia	Phase 2	US	The Sidney Kimmel Comprehensive Cancer Center	30 Jan 2017
Myelodysplastic Syndromes	Phase 2	US	The Sidney Kimmel Comprehensive Cancer Center	30 Jan 2017
Myelodysplastic Syndromes	Phase 2	US	Io Therapeutics, Inc.	30 Jan 2017
Refractory acute myeloid leukemia	Phase 2	US	The Sidney Kimmel Comprehensive Cancer Center	30 Jan 2017
Refractory acute myeloid leukemia	Phase 2	US	Io Therapeutics, Inc.	30 Jan 2017
Acute Promyelocytic Leukemia	Phase 2	US	NuRx Pharmaceuticals, Inc.	01 Apr 2008
Neutropenia	Phase 2	AU	Vitae Pharmaceuticals LLC	15 Oct 2005
Breast Cancer	Phase 2	US	Allergan Specialty Therapeutics, Inc.	13 Nov 2002
Stem cell mobilisation	Phase 2	AU	-	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02749708 (Pubmed \| Front Oncol) Manual	Phase 1	Acute Myeloid Leukemia	11	IRX 5183	(caazxhmerq) = cAE included hypertriglyceridemia, fatigue, dyspnea, and edema. 3 pts at the first dose level developed asymptomatic Grade 3 hypertriglyceridemia tppuhrfdlg (xxwtcjuvkv )	Positive	23 Oct 2020
ASCO2004	Phase 1	HR-positive/HER2-low Solid Tumors	15	AGN 195183	wfjfgbojlw(fnacnisdzo) = 2 of 4 pts treated had gr 3 elevation of alkaline phosphatase ehnpjwpuou (qzepzcxrcg ) View more	Positive	15 Jul 2004