Delving into the Latest Updates on BMS-303141 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

ACL

Action

inhibitors

Mechanism

ACL inhibitors(ATP-citrate synthase inhibitors)

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication

Dyslipidemias

Inactive Indication-

Originator Organization

Bristol Myers Squibb Co.

Active Organization

Bristol Myers Squibb Co.

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC19H15Cl2NO4S

InChIKeySIIPNDKXZOTLEA-UHFFFAOYSA-N

CAS Registry943962-47-8

Cholesterol is considered a major factor contributing to cardiovascular diseases. Statins, the most commonly prescribed cholesterol-lowering drugs, are known to have various limitations. Inhibition of Adenosine Triphosphate-Citrate Lyase (ACLY) has been proposed as an alternative therapeutic strategy for managing hypercholesterolemia by lowering cholesterol levels. This has led to the discovery of a cell-permeable small molecule ACLY inhibitor.

Methods::

ACLY enzyme activity was assessed using an ACLY Assay Kit with the ADP-Glo Kinase Assay Kit. HepG2 cells were treated with test compounds to demonstrate cholesterol and fatty acid synthesis. Pharmacokinetic studies were performed on CD-1 mice following a single oral dose of the compounds. Hypercholesterolemia was induced in mice through a High-Fat and High Cholesterol Diet (HFHCD), and drugs were administered orally for six weeks. Serum and hepatic lipid profiles were subsequently analyzed.

Results::

To increase the pharmacochemical properties, four analogues of BMS-303141, ID0018, ID0023, ID0085, and ID0106, were designed and synthesized. These compounds showed superior ACLY inhibitory activity and dose-dependent suppression of cholesterol and fatty acid synthesis in HepG2 cells. Among the analogues, ID0085 exhibited the most potent ACLY inhibition (IC50: 45 nM, 10-fold lower than BMS- 303141) and achieved near-complete suppression in cholesterol and fatty acid synthesis at the highest concentration. Pharmacokinetic studies revealed improved half-lives and systemic exposures for all analogues. In hypercholesterolemic mouse models, test compounds significantly reduced serum total cholesterol (32.0-57.3%) and low-density lipoprotein cholesterol (67.5-80.2%) levels compared to the vehicle group. Notably, ID0085 also increased high-density lipoprotein cholesterol levels.

Conclusion::

Based on the results, ID0085 appears to be the most promising therapeutic candidate for the treatment of hypercholesterolemia.

other::

Not applicable.

01 Aug 2024·Cell Chemical Biology

AspSnFR: A genetically encoded biosensor for real-time monitoring of aspartate in live cells

Article

Author: Thing-Teoh, Shao ; Superti-Furga, Giulio ; Reinhardt, Jürgen ; Chang, Lena ; Pfeifer, Martin ; Wiedmer, Tabea ; Tarnawski, Miroslaw ; Hellweg, Lars ; Kress, Jana ; Hiblot, Julien ; Johnsson, Kai ; Bergner, Andrea ; Leippe, Philipp

Aspartate is crucial for nucleotide synthesis, ammonia detoxification, and maintaining redox balance via the malate-aspartate-shuttle (MAS). To disentangle these multiple roles of aspartate metabolism, tools are required that measure aspartate concentrations in real time and in live cells. We introduce AspSnFR, a genetically encoded green fluorescent biosensor for intracellular aspartate, engineered through displaying and screening biosensor libraries on mammalian cells. In live cells, AspSnFR is able to precisely and quantitatively measure cytosolic aspartate concentrations and dissect its production from glutamine. Combining high-content imaging of AspSnFR with pharmacological perturbations exposes differences in metabolic vulnerabilities of aspartate levels based on nutrient availability. Further, AspSnFR facilitates tracking of aspartate export from mitochondria through SLC25A12, the MAS' key transporter. We show that SLC25A12 is a rapidly responding and direct route to couple Ca²⁺ signaling with mitochondrial aspartate export. This establishes SLC25A12 as a crucial link between cellular signaling, mitochondrial respiration, and metabolism.

01 May 2024·Gastroenterology

Oncogenic Fatty Acid Metabolism Rewires Energy Supply Chain in Gastric Carcinogenesis

Article

Author: Zhang, Changqing ; Caprioli, Richard M ; Jang, Bogun ; Tan, Marcus C B ; Trinh, Vincent Q ; Lee, Cheol ; Kim, Kwangho ; Lee, Su-Hyung ; Reyzer, Michelle L ; Caldwell, Brianna ; Won, Yoonkyung ; Lee, Hye Seung ; Kim, Hyesung ; Presentation, Kimberly S ; Choi, Eunyoung

BACKGROUND & AIMS:

Gastric carcinogenesis develops within a sequential carcinogenic cascade from precancerous metaplasia to dysplasia and adenocarcinoma, and oncogenic gene activation can drive the process. Metabolic reprogramming is considered a key mechanism for cancer cell growth and proliferation. However, how metabolic changes contribute to the progression of metaplasia to dysplasia remains unclear. We have examined metabolic dynamics during gastric carcinogenesis using a novel mouse model that induces Kras activation in zymogen-secreting chief cells.

METHODS:

We generated a Gif-rtTA;TetO-Cre;Kras^G12D (GCK) mouse model that continuously induces active Kras expression in chief cells after doxycycline treatment. Histologic examination and imaging mass spectrometry were performed in the GCK mouse stomachs at 2 to 14 weeks after doxycycline treatment. Mouse and human gastric organoids were used for metabolic enzyme inhibitor treatment. The GCK mice were treated with a stearoyl- coenzyme A desaturase (SCD) inhibitor to inhibit the fatty acid desaturation. Tissue microarrays were used to assess the SCD expression in human gastrointestinal cancers.

RESULTS:

The GCK mice developed metaplasia and high-grade dysplasia within 4 months. Metabolic reprogramming from glycolysis to fatty acid metabolism occurred during metaplasia progression to dysplasia. Altered fatty acid desaturation through SCD produces a novel eicosenoic acid, which fuels dysplastic cell hyperproliferation and survival. The SCD inhibitor killed both mouse and human dysplastic organoids and selectively targeted dysplastic cells in vivo. SCD was up-regulated during carcinogenesis in human gastrointestinal cancers.

CONCLUSIONS:

Active Kras expression only in gastric chief cells drives the full spectrum of gastric carcinogenesis. Also, oncogenic metabolic rewiring is an essential adaptation for high-energy demand in dysplastic cells.

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