Delving into the Latest Updates on Seliciclib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

2-(R)-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine, R-roscovitine

+ [2]

Target

CDK2 x CDK7 x CDK9

Mechanism

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

Therapeutic Areas

NeoplasmsNervous System DiseasesEndocrinology and Metabolic Disease+ [4]

Active Indication

Cushing SyndromeNasopharyngeal NeoplasmsNon-Small Cell Lung Cancer+ [1]

Inactive Indication

Advanced Malignant Solid NeoplasmBreast CancerCOVID-19+ [6]

Originator Organization

Centre National de la Recherche Scientifique

Active Organization

Centre National de la Recherche Scientifique

ManRos Therapeutics SA

Cyclacel Pharmaceuticals, Inc.

+ [1]

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC19H26N6O

InChIKeyBTIHMVBBUGXLCJ-OAHLLOKOSA-N

CAS Registry186692-46-6

A Phase II, Dose Ranging, Multicenter, Double-blind, Placebo Controlled Study to Evaluate Safety and Effects of (R)-Roscovitine in Adults Subjects With Cystic Fibrosis, Carrying 2 Cystic Fibrosis Causing Mutations With at Least One F508del-CFTR Mutation and Chronically Infected With Pseudomonas Aeruginosa, a Study Involving 36 CF Patients (24 Treated, 12 Controls). ROSCO-CF.

This is a phase II, dose ranging, multicenter, randomized, double-blind, placebo-controlled study.
The aim of this study is to assess the safety of increasing doses of roscovitine administered orally for 4 cycles of 4 consecutive days (treatment "on") separated by a 3 days treatment free period (treatment "off") in adult CF subjects with Cystic Fibrosis carrying 2 Cystic Fibrosis causing mutations with at least one F508del-CFTR mutation and chronically infected with Pseudomonas aeruginosa.
This study involved 36 Cystic Fibrosis patients: 24 treated and 12 controls.

Start Date22 Feb 2016

Sponsor / Collaborator

University Hospital of Brest

[+2]

EUCTR2015-002911-13-FR / Not yet recruitingPhase 2IIT

A Phase II, dose ranging, multicenter, double-blind, placebo controlled study to evaluate safety and efficacy of (R)-roscovitine in subjects with Cystic Fibrosis, homozygous for the F508del-CFTR mutation and chronically infected with Pseudomonas aeruginosa, a study involving 36 CF patients (24 treated, 12 controls). - ROSCO-CF

Start Date15 Sep 2015

Sponsor / Collaborator-

100 Clinical Results associated with Seliciclib

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100 Translational Medicine associated with Seliciclib

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100 Patents (Medical) associated with Seliciclib

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1,238

Literatures (Medical) associated with Seliciclib

01 Dec 2024·Bioorganic Chemistry

Novel purine derivatives as selective CDK2 inhibitors with potential anticancer activities: Design, synthesis and biological evaluation

Article

Author: Ahmed, Sarfaraz ; Teraiya, Nishith ; Kamdar, Jignesh H ; Sangani, Chetan B. ; Shah, Alpesh ; Juneja, Tanzil ; Sangani, Chetan B ; Kapadiya, Khushal ; Kamdar, Jignesh H.

Purine analogues were discovered to be inhibitors of CDK2, suggesting a potential therapeutic scaffold. This paper addresses the design, synthesis, and anticancer evaluation of purine analogues as kinase inhibitors. In the early stages of the investigation, the designed compounds demonstrated a promising docking score and greater protein-ligand stability in MD simulation than the standard, indicating a higher affinity against CDK2. Thus, we synthesised new purine analogues under simple and optimised reaction conditions. Among the studies under NCI-60, 5g and 5i were the most effective, with a percentage GI of 98.09 and 90 against OVCAR-4 and SNB-75, respectively, at a dose of 10 µM. Additionally, 5g and 5i demonstrated 7.80-fold and 1.54-fold greater cytotoxicity against PA-1 and MCF-7, with IC_50s of 1.08 µM and 3.54 µM, respectively, compared to seliciclib (8.43 µM and 5.46 µM). In addition, 5g and 5i showed selective cytotoxicity against PA-1 and MCF-7 than normal cells, with selectivity indexes of 26.40 and 15.45, respectively, as compared to the standard (SI=3.83 and 5.91). In the kinase selectivity assay, both compounds demonstrated greater affinity against CDK2 than other kinases, with IC₅₀ of 0.21 µM and 0.59 µM, in contrast to the standard (IC₅₀ = 0.63 µM). Furthermore, 5g confirmed kinase inhibition in the western blot by lowering CDK2, cyclin A2, and other downstream substrates. Moreover, it triggered cell death by apoptosis and cell cycle arrest in G2/M. Taken together, 5g merits further investigation in PKPD research to discover a potential therapeutic candidate against cancer.

01 Nov 2024·Protoplasma

Chemically induced phenotype plasticity in the unicellular zygnematophyte, Penium margaritaceum

Article

Author: Tomasi, Tawn ; Sgambettera, Gabriel ; Domozych, David S ; Lu, Iris ; Bagdan, Kaylee ; LoRicco, Josephine G ; Malone, Stuart

AbstractPhenotypic plasticity allows a plant cell to alter its structure and function in response to external pressure. This adaptive phenomenon has also been important in the evolution of plants including the emergence of land plants from a streptophyte alga. Penium margaritaceum is a unicellular zygnematophyte (i.e., the group of streptophyte algae that is sister to land plants) that was employed in order to study phenotypic plasticity with a focus on the role of subcellular expansion centers and the cell wall in this process. Live cell fluorescence labeling, immunofluorescence labeling, transmission electron microscopy, and scanning electron microscopy showed significant subcellular changes and alterations to the cell wall. When treated with the actin-perturbing agent, cytochalasin E, cytokinesis is arrested and cells are transformed into pseudo-filaments made of up to eight or more cellular units. When treated with the cyclin-dependent kinase (CDK) inhibitor, roscovitine, cells converted to a unique phenotype with a narrow isthmus zone.

01 Oct 2024·Computational Biology and Chemistry

Targeting cyclin-dependent kinase 2 CDK2: Insights from molecular docking and dynamics simulation – A systematic computational approach to discover novel cancer therapeutics

Review

Author: B, Shantha Kumar ; Muthu Kumaradoss, Kathiravan ; Karthick Raja Namasivayam, S ; Alfarhan, Ahmed ; Rajagopal, Rajakrishnan ; Arockiaraj, Jesu ; G V, Anjana ; Chagaleti, Bharath Kumar

Global public health is confronted with significant challenges due to the prevalence of cancer and the emergence of treatment resistance. This work focuses on the identification of cyclin-dependent kinase 2 (CDK2) through a systematic computational approach to discover novel cancer therapeutics. A ligand-based pharmacophore model was initially developed using a training set of seven potent CDK2 inhibitors. The obtained most robust model was characterized by three features: one donor (|Don|) and two acceptors (|Acc|). Screening this model against the ZINC database resulted in identifying 108 hits, which underwent further molecular docking studies. The docking results indicated binding affinity, with energy values ranging from -6.59 kcal mol⁻¹ to -7.40 kcal mol⁻¹ compared to the standard Roscovitine. The top 10 compounds (Z1-Z10) selected from the docking data were further screened for ADMET profiling, ensuring their compliance with pharmacokinetic and toxicological criteria. The top 3 compounds (Z1-Z3) chosen from the docking were subjected to Density Functional Theory (DFT) studies. They revealed significant variations in electronic properties, providing insights into the reactivity, stability, and polarity of these compounds. Molecular dynamics simulations confirmed the stability of the ligand-protein complexes, with acceptable RMSD and RMSF values. Specifically, compound Z1 demonstrated stability, around 2.4 Å, and maintained throughout the 100 ns simulation period with minimal conformational changes, stable RMSD, and consistent protein-ligand interactions.

100 Deals associated with Seliciclib

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External Link

KEGG	Wiki	ATC	Drug Bank
-	Seliciclib	-	DB06195

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hematologic Neoplasms	Phase 2	GB	Cyclacel Pharmaceuticals, Inc.	-
Non-Small Cell Lung Cancer	Phase 2	-	Centre National de la Recherche Scientifique	-
Non-Small Cell Lung Cancer	Phase 2	-	ManRos Therapeutics SA	-
Pituitary ACTH Hypersecretion	Phase 2	-	ManRos Therapeutics SA	-
Pituitary ACTH Hypersecretion	Phase 2	-	Cyclacel Pharmaceuticals, Inc.	-
Pituitary ACTH Hypersecretion	Phase 2	-	Centre National de la Recherche Scientifique	-
Breast Cancer	Preclinical	GB	-	-
Breast Cancer	Discovery	BE	-	-
Breast Cancer	Discovery	NL	-	-
Breast Cancer	Discovery	FR	-	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02160730 (CTgov)	Phase 2	Pituitary ACTH Hypersecretion	4	R-roscovitine	sdwgngijos(xtyighaigc) = cytudjvvcd pnxujkzqit (klxomeztuo, ptaidrlhpj - yvvosyluqd) View more	-	29 Oct 2021
TRAFIC (EULAR2020)	Phase 1	Rheumatoid Arthritis	15	Seliciclib	plhyckzzri(ijnktyzgnj) = 6 patients experienced DLTs, of which two were classified as serious AEs (SAEs) in keeping with the safety profile of seliciclib; these are summarised in Table 1. Of 43/65 total AEs reported at any dose that did not contribute to a DLT, 26 were possibly, probably or definitely related to seliciclib; 19 of these 26 were mild, 7 moderate and none severe. The most frequent AE was mild nausea. hsodzseglw (ktdnecadnj )	Positive	03 Jun 2020