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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1,240

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 ; Kapadiya, Khushal ; Sangani, Chetan B ; 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 Dec 2024·Purinergic Signalling

Molecular mechanisms of extracellular-ATP-mediated colorectal cancer progression: Implication of purinergic receptors-mediated nucleocytoplasmic shuttling of HuR

Article

Author: Shatat, Abdel-Aziz S ; Rashed, Mohammed H ; Saleh, Ibrahim G ; Mahgoup, Elsayed M ; Akool, El-Sayed

AbstractOne of the leading causes of cancer-related deaths worldwide is colorectal cancer (CRC). Extracellular ATP (e-ATP) and purinergic receptors (P2R) play a central role in CRC proliferation and progression. Human antigen R (HuR) is becoming more and more understood to be essential for the expression of genes linked to cancer. The current study demonstrates that ATP can mediate CRC (Caco-2 cells) progression via induction of HuR nucleocytoplasmic shuttling and subsequent expression of cancer-related genes, a consequence mostly mediated via the P2R receptor. It was also noted that suppression of HuR activity by using dihydrotanshinone I (DHTS) prevents cancer-related gene expression and subsequent CRC (Caco-2 cells) progression induced by ATP. The expression of cyclin A2/cyclin-dependent kinase 2 (CDK2), Bcl-2, ProT-α, hypoxia‐inducible factor1-α (HIF1-α), vascular endothelial growth factor A (VEGF-A), transforming growth factor-β (TGF-β) and matrix metallopeptidase 9 (MMP-9) induced by ATP were highly reduced in the presence of either PPADS (non-selective P2R antagonist) or DHTS. In addition, e-ATP-induced Caco-2 cell proliferation as well as cell survival were highly reduced in the presence of either PPADS or DHTS or selective CDK-2 inhibitor (Roscovitine) or selective Bcl-2 inhibitor (ABT-263). Furthermore, it was found that MMP-9 is critical for Caco-2 cells migration induced by e-ATP as demonstrated by a clear reduction in cells migration in the presence of a selective MMP-9 inhibitor (Marimastat). Collectively, these data demonstrate that ATP through P2R activation can induce HuR nucleocytoplasmic shuttling that could be translated into an increase in cancer-related genes expression and subsequent, cell proliferation and progression.

01 Nov 2024·Drug Development Research

Molecular docking, DFT and antiproliferative properties of 4‐(3,4‐dimethoxyphenyl)−3‐(4‐methoxyphenyl)−1‐phenyl‐1H‐pyrazolo[3,4‐b]pyridine as potent anticancer agent with CDK2 and PIM1 inhibition potency

Article

Author: Almansour, Basma S. ; Al‐Rashood, Sara T. ; Elgohary, Mohamed K. ; Ziedan, Noha I. ; Abdel‐Aziz, Hatem A. ; Elkotamy, Mahmoud S. ; Binjubair, Faizah A. ; Abdel‐Aziz, Alaa A.‐M.

AbstractDue to the limited effeteness and safety concerns associated with current cancer treatments, there is a pressing need to develop novel therapeutic agents. 4‐(3,4‐Dimethoxyphenyl)−3‐(4‐methoxyphenyl)−1‐phenyl‐1H‐pyrazolo[3,4‐b]pyridine (3) was synthesized and Initially screened on 59 cancer cell lines showed promising anticancer activity, so, it was chosen for a 5‐dose experiment by the NCI/USA. The GI50 values ranged from 1.04 to 8.02 μM on the entire nine panels (57 cell lines), with a GI50 of 2.70 μM for (MG‐MID) panel, indicating an encouraging action. To further explore the molecular attributes of compound 3, we optimized its structure using DFT with the B3LYP/6‐31 + + G(d,p) basis set. We have considered vibrational analysis, bond lengths and angles, FMOs, and MEP for the structure. Additionally, pharmacokinetic assessments were conducted using various in‐silico platforms to evaluate the compound safety. A molecular modeling study created a kinase profile on 44 different kinases. This allowed us to study our compound's binding affinity to these kinases and compare it to the co‐crystallized one. Our findings revealed compound 3 exhibited better binding for half of the tested kinases, suggesting its potential as a multi‐kinase inhibitor. To further validate our computational results, we tested compound 3 for its inhibitory effects on CDK2 and PIM1. Compound 3 exhibited an IC50 of 0.30 µM for CDK2 inhibition, making it five times less active than Roscovitine, which has an IC50 of 0.06 µM. However, compound 3 demonstrated slightly better inhibition of PIM1 compared to Staurosporine. These findings suggest that compound 3 is a promising anticancer agent with the potential for further development into a highly active compound.

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
Breast Cancer	Phase 2	GB	-	-
Nasopharyngeal Neoplasms	Phase 2	-	Centre National de la Recherche Scientifique	-
Nasopharyngeal Neoplasms	Phase 2	-	ManRos Therapeutics SA	-
Nasopharyngeal Neoplasms	Phase 2	-	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	-
Hematologic Neoplasms	Discovery	GB	Cyclacel Pharmaceuticals, Inc.	-

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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	sdxipeyjlf(cdkjngdvfs) = ogyxxuotee dpxzgjtvdw (pttojxwlcb, zmtlgscdqf - iozpjwmbcy) View more	-	29 Oct 2021
TRAFIC (EULAR2020)	Phase 1	Rheumatoid Arthritis	15	Seliciclib	emjfzcjihd(lnoxuzhxio) = 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. wzadokshqx (unrhijunnh )	Positive	03 Jun 2020
ASTRO	Not Applicable	DNA Damage	-	Seliciclib (S)	njwdgzdpyn(jmhgrcvwzl) = xmztsrlipw rxsoalgaty (jyycneiryv )	-	01 Nov 2010