ACS Medicinal Chemistry Letters

Journal Article

Discovery of CVN636: A Highly Potent, Selective, and CNS Penetrant mGluR7 Allosteric Agonist

Dickson, Louise; Teall, Martin; Chevalier, Elodie; Cheung, Toni; Liwicki, Gemma M.;

2023 ACS Medicinal Chemistry Letters

The low affinity metabotropic glutamate receptor mGluR7 has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the functional role and therapeutic potential of this receptor. In this work, we present the...

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Journal Article

Readily Accessible High-Throughput Experimentation: A General Protocol for the Preparation of ChemBeads and EnzyBeads

Impastato, Anna C.; Brown, Jesse T. C.; Wang, Ying; Tu, Noah P.

2023 ACS Medicinal Chemistry Letters

doi:10.1021/acsmedchemlett.2c00491

Chemical- and enzyme-coated beads (ChemBeads and EnzyBeads) were introduced recently as a universal strategy for the accurate dispensing of various solids in submilligram quantities using automated instrumentation or manual dispensing. The coated beads are prepared using a resonant acoustic...

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Journal Article

Conversion of a Cardiac Muscle Modulator from an Inhibitor to an Activator

Cai, Fangze; Kampourakis, Thomas; Parijat, Priyanka; Cockburn, Kieran T.; Sykes, Brian D.

2023 ACS Medicinal Chemistry Letters

doi:10.1021/acsmedchemlett.3c00033

The binding of calcium to cardiac troponin C (cTnC) enhances the binding of troponin I (cTnI) switch region to the regulatory domain of cTnC (cNTnC) and triggers muscle contraction. Several molecules alter the response of the sarcomere by targeting this interface; virtually all have an aromatic...

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Journal Article

A Shift in Thinking: Cellular Thermal Shift Assay-Enabled Drug Discovery

Caballero, Isabel Martín; Lundgren, Stina

2023 ACS Medicinal Chemistry Letters

doi:10.1021/acsmedchemlett.2c00545

A decade has passed since the cellular thermal shift assay (CETSA) was introduced to the drug discovery community. Over the years, the method has guided numerous projects by providing insights about, for example, target engagement, lead generation, target identification, lead optimization, and...

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Journal Article

Design, Synthesis, and Bioevaluation of Dexmedetomidine Prodrug

Li, Xin; Zhang, Jingjing; Zhou, Changcui; Ling, Rui; Gong, Deying;

2023 ACS Medicinal Chemistry Letters

doi:10.1021/acsmedchemlett.2c00449

Dexmedetomidine is commonly used in clinical practice as an anesthetic adjuvant and sedative. Unfortunately, major side effects include significant blood pressure fluctuation and bradycardia. Herein, we report the design and synthesis of four series of dexmedetomidine prodrugs aimed to alleviate...

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Journal Article

Relevance of the Trillion-Sized Chemical Space “eXplore” as a Source for Drug Discovery

Neumann, Alexander; Marrison, Lester; Klein, Raphael

2023 ACS Medicinal Chemistry Letters

doi:10.1021/acsmedchemlett.3c00021

Within the past two decades, virtual combinatorial compound collections, so-called chemical spaces, became an important molecule source for pharmaceutical research all over the world. The emergence of compound vendor chemical spaces with rapidly growing numbers of molecules raises questions...

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Journal Article

Discovery of Futibatinib: The First Covalent FGFR Kinase Inhibitor in Clinical Use

Ito, Satoru; Otsuki, Sachie; Ohsawa, Hirokazu; Hirano, Atsushi; Kazuno, Hideki;

2023 ACS Medicinal Chemistry Letters

doi:10.1021/acsmedchemlett.3c00006

Deregulating fibroblast growth factor receptor (FGFR) signaling is a promising strategy for cancer therapy. Herein, we report the discovery of compound 5 (TAS-120, futibatinib), a potent and selective covalent inhibitor of FGFR1–4, starting from a unique dual inhibitor of mutant epidermal growth...

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Journal Article

Targeting the “Undruggable” Driver Protein, KRASG12D, as Potential Therapy in Prostate Cancer

Kargbo, Robert B.

2023 ACS Medicinal Chemistry Letters

doi:10.1021/acsmedchemlett.3c00076

In spite of the progress made in the development of KRASG12C inhibitors, there is still continued interest to develop inhibitors of other KRAS such as KRASG12D for the treatment of diseases, including prostate cancer, colorectal cancer, and non-small-cell lung cancer. This Patent Highlight...

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Journal Article

Discovery of a Potent and Selective Naphthyridine-Based Chemical Probe for Casein Kinase 2

Davis-Gilbert, Zachary W.; Krämer, Andreas; Dunford, James E.; Howell, Stefanie; Senbabaoglu, Filiz;

2023 ACS Medicinal Chemistry Letters

doi:10.1021/acsmedchemlett.2c00530

Naphthyridine-based inhibitors were synthesized to yield a potent and cell-active inhibitor of casein kinase 2 (CK2). Compound 2 selectively inhibits CK2α and CK2α′ when profiled broadly, thereby making it an exquisitely selective chemical probe for CK2. A negative control that is structurally...

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Journal Article

The Identification of GPR52 Agonist HTL0041178, a Potential Therapy for Schizophrenia and Related Psychiatric Disorders

Poulter, Simon; Austin, Nigel; Armstrong, Rachel; Barnes, Matt; Bucknell, Sarah Joanne;

2023 ACS Medicinal Chemistry Letters

doi:10.1021/acsmedchemlett.3c00052

HTL0041178 (1), a potent GPR52 agonist with a promising pharmacokinetic profile and exhibiting oral activity in preclinical models, has been identified. This molecule was the outcome of a judicious molecular property-based optimization approach, focusing on balancing potency against metabolic...

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