Delving into the Latest Updates on TS-032 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

PF-04802540, PF-4802540, PF4802540

+ [1]

Target

mGluRs

Action

agonists

Mechanism

mGluRs agonists(Metabotropic glutamate receptor agonists)

Therapeutic Areas

Nervous System Diseases

Active Indication-

Inactive Indication

Schizophrenia

Originator Organization

Taisho Pharmaceutical Co., Ltd.

Active Organization-

Inactive Organization

Taisho Pharmaceutical Co., Ltd.

Pfizer Inc.

Drug Highest PhaseDiscontinuedPhase 1

First Approval Date-

Regulation-

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Approximately half of melanoma tumors lack a druggable target and are unresponsive to current targeted therapeutics. One proposed approach for treating these therapeutically orphaned tumors is by targeting transcriptional dependencies (oncogene starvation), whereby survival factors are depleted through inhibition of transcriptional regulators. A drug screen identified a CDK9 inhibitor (SNS-032) to have therapeutic selectivity against wild-type (wt) BRAF^wt/NRAS^wt melanomas compared with BRAF^mut/NRAS^mut mutated melanomas. We then used two strategies to inhibit CDK9 in vitro-a CDK9 degrader (TS-032) and a selective CDK9 kinase inhibitor (NVP-2). At 500 nM, both TS-032 and NVP-2 demonstrated greater suppression of BRAF^wt/NRAS^wt/NF1^wt cutaneous and uveal melanomas than mutant melanomas. RNA sequencing analysis of eight melanoma lines with NVP-2 treatment demonstrated that the context of this vulnerability appears to converge on a cell cycle network that includes many transcriptional regulators, such as the E2F family members. The Cancer Genome Atlas human melanoma tumor data further supported a potential oncogenic role for E2F1 and E2F2 in BRAF^wt/NRAS^wt/NF1^wt tumors and a direct link to CDK9. Our results suggest that transcriptional blockade through selective targeting of CDK9 is an effective method of suppressing therapeutically orphaned BRAF/NRAS/NF1 wt melanomas.

01 Feb 2021·Mini reviews in medicinal chemistryQ3 · MEDICINE

The Recent Development of Piperazine and Piperidine Derivatives as Antipsychotic Agents

Q3 · MEDICINE

Review

Author: Bhattacharya, Sushanta ; Parwani, Deepa ; Rathore, Akash ; Mallick, Chaitali ; Agarwal, Shivangi ; Asati, Vivek ; Kashaw, Sushil Kumar

Schizophrenia is a chronic neuropsychiatric disorder that affects nearly 1% of the global population. There are various anti-psychotic drugs available for the treatment of schizophrenia, but they have certain side effects; therefore, there is a need to explore and develop novel potential lead compounds against schizophrenia. The currently available drugs e.g. typical and atypical antipsychotics act on different dopamine and serotonin receptors and as per literature reports, various piperidine and piperazine derivatives have shown promising activity against these receptors. When different heterocyclic groups are attached to basic piperidine and piperazine rings, the antipsychotic activity is greatly potentiated. In this direction, various antipsychotic drugs have been synthesized at the laboratory level, and few are under clinical trial studies, such as Lu AE58054, PF-04802540, ORG25935, DMXB-A, Bitopertin, and ABT-126. In the present review, we include the studies related to the effect of different substituents on piperidine/piperazine derivatives and their anti-psychotic activity. Various series of synthesized compounds by other researchers with piperidine/piperazine nucleus have been reviewed and diagrammatically represented in the form of SAR (structure-activity relationships), which will help the scientists for the development of potential lead compounds.

100 Deals associated with TS-032

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