Delving into the Latest Updates on VTP-195183 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [4]

Target

RARα

Action

agonists

Mechanism

RARα agonists(Retinoic acid receptor alpha agonists)

Therapeutic Areas

NeoplasmsImmune System DiseasesCardiovascular Diseases+ [1]

Active Indication

Acute Myeloid LeukemiaMultiple Myeloma

Inactive Indication

Acute Promyelocytic LeukemiaBreast CancerChronic Myelomonocytic Leukemia+ [6]

Originator Organization

Allergan UC

Active Organization

Io Therapeutics, Inc.

Inactive Organization

The Sidney Kimmel Comprehensive Cancer CenterAllergan Specialty Therapeutics, Inc.NuRx Pharmaceuticals, Inc.

+ [1]

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

Login to view timeline

Structure/Sequence

Molecular FormulaC22H22ClF2NO4

InChIKeyPNAWUIKCVQSLFG-UHFFFAOYSA-N

CAS Registry367273-07-2

A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARβ, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARβ (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.

01 Feb 2017·Archivum Immunologiae et Therapiae ExperimentalisQ4 · MEDICINE

Antagonizing Retinoic Acid Receptors Increases Myeloid Cell Production by Cultured Human Hematopoietic Stem Cells

Q4 · MEDICINE

Article

Author: Brown, Geoffrey ; Marcinkowska, Ewa ; Marchwicka, Aleksandra ; Cunningham, Alan ; Toellner, Kai-Michael

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 Nov 2013·British Journal of Pharmacology

An in vitro model for the pro‐fibrotic effects of retinoids: mechanisms of action

Article

Author: Hendry, B M ; Corcoran, J P ; Xu, Q ; Rankin, A C

Background and PurposeRetinoids, including all‐trans retinoic acid (tRA), have dose‐dependent pro‐fibrotic effects in experimental kidney diseases. To understand and eventually prevent such adverse effects, it is important to establish relevant in vitro models and unravel their mechanisms.Experimental ApproachFibrogenic effects of retinoids were assessed in NRK‐49F renal fibroblasts using picro‐Sirius red staining for collagens and quantified by spectrophotometric analysis of the eluted stain. Other methods included RT‐qPCR, immunoassays and matrix metalloproteinase (MMP) activity assays.Key ResultsWith or without TGF‐β1, tRA was dose‐dependently pro‐fibrotic, notably increasing collagen accumulation. tRA and TGF‐β1 additively suppressed expression of mRNA for MMP2, 3 and 13 and suppressed MMP activity. tRA, in the presence of TGF‐β1, induced plasminogen activator inhibitor‐1 (PAI‐1) mRNA and they additively induced PAI‐1 protein expression. A PAI‐1 inhibitor, a pan‐retinoic acid receptor (RAR) antagonist and a pan‐retinoid X receptor (RXR) antagonist each partially prevented the pro‐fibrotic effect of tRA. The dose‐dependent pro‐fibrotic effects of a pan‐RXR agonist were similar to those of tRA. A pan‐RAR agonist showed weaker, less dose‐dependent pro‐fibrotic effects and the pro‐fibrotic effects of RARα and RARβ‐selective agonists were even smaller. An RARγ‐selective agonist did not affect fibrogenesis.Conclusions and ImplicationsAn in vitro model for the pro‐fibrotic effects of retinoids was established in NRK‐49F cells. It was associated with reduced MMP activity and increased PAI‐1 expression, and was probably mediated by RXR and RAR. To avoid or antagonize the pro‐fibrotic activity of tRA, further studies on RAR isotype‐selective agonists and PAI‐1 inhibitors might be of value.

100 Deals associated with VTP-195183

Login to view more data

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB05653

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Phase 1	-	Io Therapeutics, Inc.	-
Multiple Myeloma	Phase 1	-	Io Therapeutics, Inc.	-
Chronic Myelomonocytic Leukemia	Preclinical	United States	The Sidney Kimmel Comprehensive Cancer Center	30 Jan 2017
Chronic Myelomonocytic Leukemia	Preclinical	United States	Io Therapeutics, Inc.	30 Jan 2017
Relapsing acute myeloid leukemia	Preclinical	United States	The Sidney Kimmel Comprehensive Cancer Center	30 Jan 2017
Relapsing acute myeloid leukemia	Preclinical	United States	Io Therapeutics, Inc.	30 Jan 2017
Neutropenia	Preclinical	Australia	Vitae Pharmaceuticals LLC	15 Oct 2005
Stem cell mobilisation	Preclinical	Australia	-	-
Acute Promyelocytic Leukemia	Discovery	United States	NuRx Pharmaceuticals, Inc.	01 Apr 2008
Breast Cancer	Discovery	United States	Allergan Specialty Therapeutics, Inc.	13 Nov 2002

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


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