Delving into the Latest Updates on SNS-032 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Mechanism

CDK2 inhibitors(Cyclin-dependent kinase 2 inhibitors), CDK7 inhibitors(Cyclin-dependent kinase 7 inhibitors), CDK9 inhibitors(Cyclin-dependent kinase 9 inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesCardiovascular Diseases+ [1]

Active Indication-

Inactive Indication

Advanced Malignant Solid NeoplasmCD19 Expressing MalignanciesChronic Lymphocytic Leukemia+ [3]

Originator Organization

Bristol Myers Squibb Co.

Active Organization-

Inactive Organization

Sunesis Pharmaceuticals, Inc.

Bristol Myers Squibb Co.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC17H24N4O2S2

InChIKeyOUSFTKFNBAZUKL-UHFFFAOYSA-N

CAS Registry345627-80-7

Human constitutive androstane receptor (hCAR) regulates xenobiotic metabolism. Its large and flexible ligand binding pocket can accommodate structurally diverse compounds. An assay for characterizing the binding of ligands to hCAR is needed but has not been reported. Here, we first discovered the promiscuous kinase inhibitor SNS-032 and its derivative THAL-SNS-032 as binders of hCAR, then developed BODIPY FL SNS 032 (14) as a high-affinity hCAR fluorescent probe (K _d: 300 ± 30 nM) in a TR-FRET binding assay and used it to characterize hCAR ligands for their competitive binding activities. BODIPY FL SNS 032 also displayed high binding affinities to multiple kinases, such as hGSK3A (K _d: 4.5 ± 0.2 nM), hCDK9/CycT1 (K _d: 5.1 ± 0.6 nM), hMAPK15 (K _d: 340 ± 20 nM), hCASK (K _d: 550 ± 30 nM), and hCAMKK2 (K _d: 530 ± 40 nM). BODIPY FL SNS 032 is therefore a versatile probe for hCAR and multiple kinases.

05 Jan 2024·Neuro-Oncology

CDK7 and CDK9 inhibition interferes with transcription, translation, and stemness, and induces cytotoxicity in GBM irrespective of temozolomide sensitivity

Article

Author: Khambati, Fatema ; Lawrence, Harshani ; Mo, Qianxing ; Tiek, Deanna M ; Padmanabhan, Jaya ; Bhutada, Isha ; Duckett, Derek ; Cheng, Shi-Yuan ; Chellappan, Srikumar P ; Vogelbaum, Michael A

AbstractBackgroundGlioblastoma (GBM) is refractory to current treatment modalities while side effects of treatments result in neurotoxicity and cognitive impairment. Here we test the hypothesis that inhibiting CDK7 or CDK9 would effectively combat GBM with reduced neurotoxicity.MethodsWe examined the effect of a CDK7 inhibitor, THZ1, and multiple CDK9 inhibitors (SNS032, AZD4573, NVP2, and JSH150) on GBM cell lines, patient-derived temozolomide (TMZ)-resistant and responsive primary tumor cells and glioma stem cells (GSCs). Biochemical changes were assessed by western blotting, immunofluorescence, multispectral imaging, and RT-PCR. In vivo, efficacy was assessed in orthotopic and subcutaneous xenograft models.ResultsCDK7 and CDK9 inhibitors suppressed the viability of TMZ-responsive and resistant GBM cells and GSCs at low nanomolar concentrations, with limited cytotoxic effects in vivo. The inhibitors abrogated RNA Pol II and p70S6K phosphorylation and nascent protein synthesis. Furthermore, the self-renewal of GSCs was significantly reduced with a corresponding reduction in Sox2 and Sox9 levels. Analysis of TCGA data showed increased expression of CDK7, CDK9, SOX2, SOX9, and RPS6KB1 in GBM; supporting this, multispectral imaging of a TMA revealed increased levels of CDK9, Sox2, Sox9, phospho-S6, and phospho-p70S6K in GBM compared to normal brains. RNA-Seq results suggested that inhibitors suppressed tumor-promoting genes while inducing tumor-suppressive genes. Furthermore, the studies conducted on subcutaneous and orthotopic GBM tumor xenograft models showed that administration of CDK9 inhibitors markedly suppressed tumor growth in vivo.ConclusionsOur results suggest that CDK7 and CDK9 targeted therapies may be effective against TMZ-sensitive and resistant GBM.

28 Sep 2023·Journal of medicinal chemistryQ1 · MEDICINE

Degradation of Cyclin-Dependent Kinase 9/Cyclin T1 by Optimized Microtubule-Associated Protein 1 Light Chain 3 Beta-Recruiting Coumarin Analogs.

Q1 · MEDICINE

Article

Author: Hu, Youhong ; Chen, Yi ; Gao, Yinglei ; Wei, Fan ; Zeng, Yanping ; Xiao, Jian ; Xu, Yuanxin ; Tian, Lina

Autophagy is an efficient and attractive protein degradation pathway in addition to the ubiquitin-proteasome system. Herein, systematic optimization of coumarin analogs linked with the CDK9 inhibitor SNS-032 is reported that may bind to cyclin-dependent kinase 9 (CDK9) and microtubule-associated protein 1 light chain 3 beta (LC3B) simultaneously, which leads to the selective autophagic degradation of targeted CDK9/cyclin T1 and is different from the PROTAC degrader THAL-SNS-032. Further mechanism studies revealed an autophagy-lysosome pathway, where the degraders possibly formed a ternary complex with CDK9 and LC3B. In addition, degrader 10 showed antitumor efficacy in vivo. Our work optimized a potent LC3B recruiter and demonstrated the feasibility of autophagy-tethering compounds (ATTECs), which could be applied for the degradation of diverse intracellular pathogenic proteins to treat related diseases.

100 Deals associated with SNS-032

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB05969

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
CD19 Expressing Malignancies	Phase 2	US	Sunesis Pharmaceuticals, Inc.	01 Feb 2007
Chronic Lymphocytic Leukemia	Phase 2	US	Sunesis Pharmaceuticals, Inc.	01 Feb 2007
Mantle-Cell Lymphoma	Phase 2	US	Sunesis Pharmaceuticals, Inc.	01 Feb 2007
Advanced Malignant Solid Neoplasm	Phase 2	US	Sunesis Pharmaceuticals, Inc.	01 Jan 2006
Multiple Myeloma	Phase 2	-	Bristol Myers Squibb Co.	-
Multiple Myeloma	Phase 2	-	Sunesis Pharmaceuticals, Inc.	-
Multiple Myeloma	Phase 2	-	Sunesis Pharmaceuticals, Inc.	-
Multiple Myeloma	Phase 2	-	Bristol Myers Squibb Co.	-
Solid tumor	Phase 2	US	Sunesis Pharmaceuticals, Inc.	-