Author: Natani, Sirisha ; Oudejans, Lieve ; Gallipoli, Paolo ; Cutillas, Pedro ; Copland Iii, John A ; Durko, Jozef ; Boet, Emeline ; Rio-Machin, Ana ; von Kriegsheim, Alex ; Yuneva, Mariia ; Austin, Michael J ; Magee, Aoife M S ; Hazlehurst, Lori ; Fitzgibbon, Jude ; Finch, Andrew J ; Burt, Richard ; Lawson, Hannah ; Tamburini, Jerome ; Woodley, Keith ; Bewicke-Copley, Findlay ; Dembitz, Vilma ; Peck, Barrie ; James, Sophie C ; Kranc, Kamil ; Rouault-Pierre, Kevin ; Rodriguez Blanco, Giovanny ; Sarry, Jean-Emmanuel ; Casado, Pedro ; Wang, Lydia M ; Schwaller, Juerg ; Atkinson, Samantha ; Patel, Bela ; Philippe, Céline ; Campos, Joana ; Pereira-Martins, Diego ; Schuringa, Jan Jacob

AbstractIdentification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients’ outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their full therapeutic potential.

07 Aug 2023·Molecular pharmaceutics

Radiosynthesis and Preliminary Evaluation of [¹¹C]SSI-4 for the Positron Emission Tomography Imaging of Stearoyl CoA Desaturase 1.

Article

Author: Li, Kang-Po ; Cai, Hancheng ; Parent, Ephraim E ; Knight, Joshua A ; Copland, John A ; Gleba, Justyna J

Stearoyl CoA desaturase 1 (SCD1) is the rate-limiting enzyme for converting saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs) and plays a key role in endogenous (de novo) fatty acid metabolism. Given that this pathway is broadly upregulated across many tumor types with an aggressive phenotype, SCD1 has emerged as a compelling target for cancer imaging and therapy. The ligand 2-(4-(2-chlorophenoxy)piperidine-1-carboxamido)-N-methylisonicotinamide (SSI-4) was identified as a potent and highly specific SCD1 inhibitor with a strong binding affinity for SCD1 at our laboratory. We herein report the radiosynthesis of [¹¹C]SSI-4 and the preliminary biological evaluation including in vivo PET imaging of SCD1 in a human tumor xenograft model. Radiotracer [¹¹C]SSI-4 was labeled at the carbamide position via the direct [¹¹C]CO₂ fixation on the Synthra MeIplus module in high molar activity and good radiochemical yield. In vitro cell uptake assays were performed with three hepatocellular carcinoma (HCC) cell lines and three renal cell carcinoma (RCC) cell lines. Additionally, in vivo small animal PET/CT imaging with [¹¹C]SSI-4 and the biodistribution were carried out in a mouse model bearing HCC xenografts. Radiotracer [¹¹C]SSI-4 afforded a 4.14 ± 0.44% (decay uncorrected, n = 10) radiochemical yield based on starting [¹¹]CO₂ radioactivity. The [¹¹C]SSI-4 radiosynthesis time including HPLC purification and SPE formulation was 25 min from the end of bombardment to the end of synthesis (EOS). The radiochemical purity of [¹¹C]SSI-4 was 98.45 ± 1.43% (n = 10) with a molar activity of 225.82 ± 33.54 GBq/μmol (6.10 ± 0.91 Ci/μmol) at the EOS. In vitro cell uptake study indicated all SSI-4 responsive HCC and RCC cell line uptakes demonstrate specific uptake and are blocked by standard compound SSI-4. Preliminary small animal PET/CT imaging study showed high specific uptake and block of [¹¹C]SSI-4 uptake with co-injection of cold SSI-4 in high SCD1-expressing organs including lacrimal gland, brown fat, liver, and tumor. In summary, novel radiotracer [¹¹C]SSI-4 was rapidly and automatedly radiosynthesized by direct [¹¹C]CO₂ fixation. Our preliminary biological evaluation results suggest [¹¹C]SSI-4 could be a promising radiotracer for PET imaging of SCD1 overexpressing tumor tissues.

02 Jan 2022·Expert Review of Medical DevicesQ3 · ENGINEERING & TECHNOLOGY

Evaluating adaptation effect in real versus virtual reality environments with people who stutter

Q3 · ENGINEERING & TECHNOLOGY

Article

Author: Almudhi, Abdulaziz

INTRODUCTIONThe adaptation effect refers to the gradual reduction of dysfluencies with repeated exposure to a substance. The concept of adaptation was originally defined in light of the reading task. Yet, limited studies have also confirmed the adaptation effect in spontaneous-speech. The reduction in the dysfluencies can be attributed to the reduction in the anxiety, or getting habituated to the content of reading material or due to motor learning.METHODSThis research aimed at measuring the adaptation effect in real and virtual reality (VR) environments for spontaneous-speech and reading. The objectives were divided into two categories. The first objective aimed at comparing the adaption effect for the real and VR environments on the reading task, while the second objective addressed the same objective, but for the spontaneous-speech task. The study involved 24 participants in the age range of 19-33 years. SSI-4 was administered on the participants.CONCLUSIONThe reduction in dysfluencies was seen for both real and VR testing environments. The reduction in the dysfluency was more marked for reading-task compared to spontaneous-speech task. The results shed light on the relationship between adaptation effect and the test environment.

100 Deals associated with SSI-4

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Adult Acute Myeloblastic Leukemia	Preclinical	GB	Queen Mary University of London	09 Dec 2022
Adult Acute Myeloblastic Leukemia	Preclinical	US	Modulation Therapeutics, Inc.	09 Dec 2022

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

SSI-4

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation