A Phase 3, 16-Week, Multicenter, Randomized, Double Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of a Single Injection of Lorecivivint 0.07 mg Dose in the Target Knee Joint of Subjects With Moderate to Severe Osteoarthritis Pain of the Knee

This phase 3 study is a multicenter, randomized, double-blind, placebo-controlled study of lorecivivint injected intra-articularly (IA) into the target (most painful) knee joint of moderately to severely symptomatic osteoarthritis (OA) subjects at a single dose of 0.07 mg lorecivivint per 2 mL injection. This study will utilize standard outcomes to evaluate the safety and efficacy of lorecivivint.

Start Date18 Nov 2022

Sponsor / Collaborator

Biosplice Therapeutics, Inc.

[+1]

NCT04931667

/ TerminatedPhase 3

A 3-Year, Multicenter, Open-Label Study Evaluating the Safety, Tolerability, and Efficacy of Intra-articular Lorecivivint in Subjects With Osteoarthritis of the Knee in a Real-World Setting (STRIDES-EXTRA)

This study is designed as a 3-year, multicenter, open-label study evaluating the safety, tolerability, and efficacy of intra-articular (IA) Lorecivivint (LOR) in subjects with osteoarthritis of the knee in a real-world setting.

Start Date15 Jul 2021

Sponsor / Collaborator

Biosplice Therapeutics, Inc.

NCT04598542

/ CompletedPhase 1

Open-Label, Parallel-Arm Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Corticosteroid Intra Articular Injection Given 7 Days Before or 7 Days After Lorecivivint Intra-articular Injection Into the Knee of Healthy Volunteers

This study will be an open-label, parallel-arm study to determine if a prior intra-articular (IA) injection of lorecivivint (LOR) affects the safety, tolerability, and/or pharmacokinetics (PK) of a subsequent IA injection of the corticosteroid triamcinolone acetonide (TA) into the same knee, and to determine if a prior IA injection of TA affects the safety or tolerability of a subsequent IA injection of LOR into the same knee.

Start Date13 Oct 2020

Sponsor / Collaborator

Biosplice Therapeutics, Inc.

100 Clinical Results associated with DYRK1A x CLK2

100 Translational Medicine associated with DYRK1A x CLK2

0 Patents (Medical) associated with DYRK1A x CLK2

Literatures (Medical) associated with DYRK1A x CLK2

31 Oct 2023·Journal of virology

On a path toward a broad-spectrum anti-viral: inhibition of HIV-1 and coronavirus replication by SR kinase inhibitor harmine.

Article

Author: Shen, David ; Jahanshahi, Shahrzad ; Chabot, Benoit ; Malty, Ramy ; Clayton, Kiera ; Cheng, Ran ; Attisano, Liliana ; Koirala, Amrit ; Cabral, Tyler ; Villasmil Ocando, Alonso ; Been, Terek ; Calarco, John ; Ahmed, Choudhary ; Hernandez, Javier ; Houry, Walid A ; Mangos, Maria ; Cochrane, Alan ; Dahal, Subha ; Babu, Mohan

IMPORTANCEThis study highlights the crucial role RNA processing plays in regulating viral gene expression and replication. By targeting SR kinases, we identified harmine as a potent inhibitor of HIV-1 as well as coronavirus (HCoV-229E and multiple SARS-CoV-2 variants) replication. Harmine inhibits HIV-1 protein expression and reduces accumulation of HIV-1 RNAs in both cell lines and primary CD4⁺ T cells. Harmine also suppresses coronavirus replication post-viral entry by preferentially reducing coronavirus sub-genomic RNA accumulation. By focusing on host factors rather than viral targets, our study offers a novel approach to combating viral infections that is effective against a range of unrelated viruses. Moreover, at doses required to inhibit virus replication, harmine had limited toxicity and minimal effect on the host transcriptome. These findings support the viability of targeting host cellular processes as a means of developing broad-spectrum anti-virals.

01 Aug 2022·European Journal of Medicinal Chemistry

Development of novel conformationally restricted selective Clk1/4 inhibitors through creating an intramolecular hydrogen bond involving an imide linker

Article

Author: Hwang, Tsong-Long ; Abdel-Halim, Mohammad ; Engel, Matthias ; Abadi, Ashraf H ; Chen, Po-Jen ; ElHady, Ahmed K ; El-Gamil, Dalia S

As prime regulators of pre-mRNA alternative splicing, different Clk isoforms were found to be overexpressed in various tumour types and have received much attention recently as potential targets for cancer therapy. Several studies have reported potent small-molecule Clk1/4 inhibitors with promising cellular anti-cancer activities; however, their clinical use was generally hampered by their compromised selectivity against off-targets, mainly Clk2 and Dyrk1A. In this study, we present a novel series of N-aroylated 5-methoxybenzothiophene-2-carboxamides (imides) as potent and selective Clk1/4 inhibitors. Potency of this series was found to be mainly dependent on the presence of an intramolecular H-bond between an ortho-methoxy group and the imide NH, that stabilizes a nearly coplanar conformation of high affinity to the ATP binding pocket(s) of Clk1/4. The two most potent hits in this series, compounds 20 (4-fluoro-2-methoxy) and 31 (5-chloro-2-methoxy) had cell free Clk1 IC₅₀s of 4 and 9.7 nM, respectively, besides an unprecedented selectivity over Clk2 with 62- and 50-times higher affinities towards Clk1, respectively. 20 and 31 also exhibited remarkable selectivity over most common off-targets including Dyrk1A. Moreover, compounds 26 (2-ethoxy) and 31 showed growth inhibitory activities in T24 cancer cells with GI₅₀s of <0.1 and 1.1 μM, respectively.

01 Jul 2022·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Discovery of novel benzothiophene derivatives as potent and narrow spectrum inhibitors of DYRK1A and DYRK1B

Q4 · MEDICINE

Article

Author: Mascarello, Alessandra ; Couñago, Rafael M ; Damião, Mariana C F C B ; Segretti, Natanael D ; Takarada, Jéssica E ; Cunha, Micael R ; Serafim, Ricardo A M ; Teodoro, Bruno V M ; Fala, Angela M ; Azevedo, Hatylas ; Guimarães, Cristiano R W ; da Silva Santiago, André ; Ramos, Priscila Z ; Ferreira, Marcos A ; Ishikawa, Eloisa E ; Godoi, Paulo H

The discovery of potent and selective inhibitors for understudied kinases can provide relevant pharmacological tools to illuminate their biological functions. DYRK1A and DYRK1B are protein kinases linked to chronic human diseases. Current DYRK1A/DYRK1B inhibitors also antagonize the function of related protein kinases, such as CDC2-like kinases (CLK1, CLK2, CLK4) and DYRK2. Here, we reveal narrow spectrum dual inhibitors of DYRK1A and DYRK1B based on a benzothiophene scaffold. Compound optimization exploited structural differences in the ATP-binding sites of the DYRK1 kinases and resulted in the discovery of 3n, a potent and cell-permeable DYRK1A/DYRK1B inhibitor. This compound has a different scaffold and a narrower off-target profile compared to current DYRK1A/DYRK1B inhibitors. We expect the benzothiophene derivatives described here to aid establishing DYRK1A/DYRK1B cellular functions and their role in human pathologies.

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