Delving into the Latest Updates on SNS-032 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

CDK2 x CDK7 x CDK9

Action

inhibitors

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 DiseasesHemic and Lymphatic Diseases

Active Indication-

Inactive Indication

Advanced Malignant Solid NeoplasmCD19 Expressing MalignanciesChronic Lymphocytic Leukemia+ [2]

Originator Organization

Bristol Myers Squibb Co.

Active Organization-

Inactive Organization

Sunesis Pharmaceuticals, Inc.

License Organization

Sunesis Pharmaceuticals, Inc.

Bristol Myers Squibb Co.

Drug Highest PhasePendingPhase 1

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC17H24N4O2S2

InChIKeyOUSFTKFNBAZUKL-UHFFFAOYSA-N

CAS Registry345627-80-7

The inhibition of cyclin-dependent kinases is a viable anticancer therapy due to their critical function in regulating cell cycle progression and transcription. The present study intended to design novel benzothiazolyl piperidine-3-carboxamide derivatives as multi-target CDKs and VEGFR2 inhibitor. Novel benzothiazolyl piperidine-3-carboxamide derivatives varying smaller and bulkier N-substitution at piperidine motif (4a-f) were designed based on the key structural features of SNS-032 (a CDK and VEGFR2 inhibitor). The compounds were subjected to extra-precision docking on seven CDKs and VEGFR2 kinase targets. The results revealed superior score/interaction of compounds with three CDKs (CDK2, CDK5, and CDK6) and VEGFR2, as compared to SNS-032. The best poses of 3, 4b, 4c and SNS-032 were used in WaterMap study to analyze the hydration sites. MD simulations (100 ns) in the TIP3P water model for 4c and SNS-032 were performed to analyze the trajectories for the deviation, fluctuations and intermolecular interaction, followed by the binding free energy calculations (MM-GBSA). All the compounds were synthesized and spectroscopically characterized by NMR, HPLC and LC-MS. In vitro CDKs (CDK2, CDK5, and CDK6) and VEGFR2 kinase inhibition assays revealed higher potency of compounds 3 (IC₅₀ 0.026 µM) and 4c (IC₅₀ 0.048 µM) as compared to SNS-032 (IC₅₀ 0.052 µM) against CDK2, compounds 3 (IC₅₀ 0.315 µM), 4a (IC₅₀ 0.248 µM), 4b (IC₅₀ 0.276 µM), and 4c (IC₅₀ 0.338 µM) as compared to SNS-032 (IC₅₀ 0.476 µM) against CDK5, compounds 3 (IC₅₀ 0.221 µM), 4a (IC₅₀ 0.256 µM), 4b (IC₅₀ 0.282 µM), 4c (IC₅₀ 0.236 µM), and 4e (IC₅₀ 0.274 µM) as compared to SNS-032 (IC₅₀ 0.365 µM) against CDK6, and comparable potency of compound 4b (IC₅₀ 0.136 µM) with Sorafenib (IC₅₀ 0.114 µM) against VEGFR2. Furthermore, anticancer screening of compounds (3 and 4a-f) was performed against NCI (USA) 60 cancer cell lines by sulforhodamine B (SRB) colorimetric assay that revealed good to excellent anticancer activity.

01 Apr 2025·European Journal of Medicinal Chemistry

Discovery of 2,4-quinazolinedione derivatives as LC3B recruiters in the facilitation of protein complex degradations

Article

Author: Zhang, Naixia ; Zhong, Chao ; Dong, Xiao ; Zeng, Yanping ; Li, Yangsha ; Chen, Yi ; Zhou, Jiayun ; Hou, Haiyang ; Shi, Li ; Hu, Youhong ; Xiao, Jian ; Xu, Yuanxin ; Fang, Yanfen ; Cheng, Gang

Targeted protein degradation through autophagosome-tethering compounds (ATTECs) that bypasses the ubiquitination process has garnered increasing attention. LC3B, a key protein in autophagosome formation, recruits substrates into the autophagy-lysosome system for degradation. In this study, we systematically optimized 2,4-quinazolinedione derivatives as LC3B-recruiting fragments, utilizing the CDK9 indicator. By attaching the designed LC3B-recruiting fragment to CDK9 inhibitor SNS-032 through a linker, the resulting bifunctional ATTEC molecule simultaneously degraded CDK9 and its associated Cyclin T1. Two-dimensional NMR experiments confirmed the direct interaction between the novel LC3B-recruiting fragments and LC3B. Mechanistic studies elucidated that degradation occurred via an LC3B-dependent autophagy-lysosomal pathway. Additionally, the general applicability of leveraging LC3B-recruiting fragments linked to inhibitors for the targeted degradation of protein complexes was validated with PRC2 and CDK2/4/6 along with their respective Cyclins. This work provides a series of novel LC3B-recruiting fragments that enrich the ATTEC toolbox and can be applied to the degradation of diverse intracellular disease-causing proteins.

01 Apr 2025·Journal of Pharmaceutical Sciences

Optimization of HPLC method for determination of Abraham solvation parameters of pharmaceuticals

Article

Author: Knašienė, Birutė ; Sadaunykas, Audrius ; Sazonovas, Andrius ; Balčiūnas, Simonas ; Naujalis, Evaldas ; Lanevskij, Kiril

Abraham solvation equation (Absolv) is a popular and well-established approach for modeling solute partitioning between phases of different polarity, which finds its applications in both organic chemistry and biomedical fields. Parameters constituting this equation are good quantitative descriptors of solute hydrogen bonding potential that are useful for QSAR modeling of more complex chemical and biological phenomena. Numerous studies dealing with fast determination of Abraham descriptors using HPLC can be found in the literature, but these mostly focus on small un-ionizable industrial and environmental chemicals, whereas experimental data for pharmaceutical molecules are clearly lacking. In the current study we build upon a previously published chromatographic approach, aiming to adapt the method to ionizable drug-like compounds, and optimize it by reducing the number of required HPLC columns. The analysis involves determination of the overall H-bond acidity (A), H-bond basicity (B) and polarity/polarizability (S) descriptors for 62 pharmaceutical molecules with previously unpublished parameter values.

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 1	United States	Sunesis Pharmaceuticals, Inc.	01 Feb 2007
Chronic Lymphocytic Leukemia	Phase 1	United States	Sunesis Pharmaceuticals, Inc.	01 Feb 2007
Mantle-Cell Lymphoma	Phase 1	United States	Sunesis Pharmaceuticals, Inc.	01 Feb 2007
Multiple Myeloma	Phase 1	United States	Sunesis Pharmaceuticals, Inc.	01 Feb 2007
Advanced Malignant Solid Neoplasm	Phase 1	United States	Sunesis Pharmaceuticals, Inc.	01 Jan 2006