Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor

Tamanini, Emiliano; Miyamura, Shin; Buck, Ildiko M.; Cons, Benjamin D.; Dawson, Lee A.; East, Charlotte; Futamura, Takashi; Goto, Shintaro; Griffiths‐Jones, Charlotte M.; Hashimoto, Tsuyoshi; Heightman, Tom D.; Ito, Hideki; Kaneko, Yosuke; Kawato, Tatsuya; Kondo, Kazumi; Kurihara, Naoki; McCarthy, J. Michael; Mori, Yoshio; Nagase, Tsuyoshi; Nakaishi, Yuichiro; Reeks, Judith; Sato, Ayumu; Schöpf, Patrick; Tai, Kuninori; Tamai, Toshiyuki; Tisi, Dominic; Woolford, Alison J.-A.

doi:10.1021/acsmedchemlett.2c00272

Cited by 6 publications

(5 citation statements)

References 29 publications

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“…The largest proportion of entries, 44% (entries 4–11), – were forinhibitors of other enzymes, which is slightly above the global average (35%). Included in this section of Table are two clinical candidates: the first, MRTX1719 (entry 6), targets an inactive form of PRMT5 where the lead compound is an impressive 8 orders of magnitude more potent than the starting fragment, and the second, MK-8189 (entry 10), is a phosphodiesterase 10 A inhibitor.…”

Section: Resultsmentioning

confidence: 88%

Fragment-to-Lead Medicinal Chemistry Publications in 2022

Woodhead,

Erlanson,

de Esch

et al. 2024

J. Med. Chem.

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This Perspective is the eighth in an annual series that summarizes successful fragment-to-lead (F2L) case studies published each year. A tabulated summary of relevant articles published in 2022 is provided, and features such as target class, screening methods, and ligand efficiency are discussed both for the 2022 examples and for the combined examples over the years 2015−2022. In addition, trends and new developments in the field are summarized. In 2022, 18 publications described successful fragment-to-lead studies, including the development of three clinical compounds (MTRX1719, MK-8189, and BI-823911). ■ SIGNIFICANCEFragment-based methodologies have become firmly established within the drug discovery community, and with the recent FDA approval of capivasertib, there are now seven fragment-derived drugs approved for clinical use. This Perspective provides case studies of successful fragment-tolead examples for 2022 and discusses various trends, including target classes, screening methods, and physicochemical properties, compared with previous years.

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Section: Resultsmentioning

confidence: 88%

Fragment-to-Lead Medicinal Chemistry Publications in 2022

Woodhead,

Erlanson,

de Esch

et al. 2024

J. Med. Chem.

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“… Structures are present in the tables corresponding to the molecules [ 9 , 14 , 19 , 21 – 23 , 42 , 43 , 45 – 50 , 52 , 56 , 57 , 60 – 68 , 71 , 73 , 74 , 78 , 80 – 91 ]. *: Ki value reported in place of an IC 50 ; NI: no inhibition observed; -: not applicable …”

Section: Discussionmentioning

confidence: 99%

“…Finally, compound 13, an orally active, brain-penetrant HDAC2 inhibitor, has recently been discovered through fragment-based drug discovery [ 91 ]. CNS penetrance is important for targeting neurological diseases such as Alzheimer’s disease where HDAC2 and HDAC3 activities are elevated [ 91 ]. Compound 13 has an FT group (chlorobenzene) that allows for HDAC2 selectivity.…”

Section: Current Class I Hdacis In the Literaturementioning

confidence: 99%

“…Compound 12 has picomolar potency towards class I HDACs which is likely due to the improved optimization of the cap group, and the visibly close resemblance of the ZBG to hydroxamates, which are intrinsically quite potent against all HDACs. Finally, compound 13, an orally active, brain-penetrant HDAC2 inhibitor, has recently been discovered through fragment-based drug discovery [91]. CNS penetrance is important for targeting neurological diseases such as Alzheimer's disease where HDAC2 and HDAC3 activities are elevated [91].…”

Section: Novel Zbgsmentioning

confidence: 99%

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Medicinal chemistry advances in targeting class I histone deacetylases

Abdallah,

de Araujo,

Patel

et al. 2023

Exploration of Targeted Anti-Tumor Therapy

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Histone deacetylases (HDACs) are a class of zinc (Zn)-dependent metalloenzymes that are responsible for epigenetic modifications. HDACs are largely associated with histone proteins that regulate gene expression at the DNA level. This tight regulation is controlled by acetylation [via histone acetyl transferases (HATs)] and deacetylation (via HDACs) of histone and non-histone proteins that alter the coiling state of DNA, thus impacting gene expression as a downstream effect. For the last two decades, HDACs have been studied extensively and indicated in a range of diseases where HDAC dysregulation has been strongly correlated with disease emergence and progression—most prominently, cancer, neurodegenerative diseases, HIV, and inflammatory diseases. The involvement of HDACs as regulators in these biochemical pathways established them as an attractive therapeutic target. This review summarizes the drug development efforts exerted to create HDAC inhibitors (HDACis), specifically class I HDACs, with a focus on the medicinal chemistry, structural design, and pharmacology aspects of these inhibitors.

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“…This phenomenon leads to a reduction in the acetylation of histones and a decrease in the expression of critical genes associated with the processes of learning and memory. The effects observed in CK-p25 mice are mitigated through HDAC2 knockdown, leading to an upregulation of crucial genes, an augmentation of synaptic plasticity, and eliminating memory deficits linked to neurodegeneration [9].…”

Section: Introductionmentioning

confidence: 99%

In Silico Identification of Novel HDAC2 Inhibitors for Reinstating Synaptic wiring in Autism Spectrum Disorder

Alharbi

2024

Adv. life sci.

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Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an increasing incidence rate. For the treatment of ASD, several pharmaceutical approaches, dietary supplements, and behavioral therapy have been proposed, but a definitive cure remains elusive. Histone deacetylases (HDACs) are critical epigenetic regulators whose molecular and pharmacological roles are being studied extensively in medically significant ailments such as neuropsychiatric disorders, neurodegenerative diseases, and cancer on a global scale. HDAC2's specific expression pattern in CNS makes it an appealing therapeutic target for neurological illnesses such as ASD.Methods: The study used PyRx software (version 0.8) to screen a library of 401 alkaloid compounds against HDAC2. In addition, the DS software was used to predict the physicochemical and DMET properties of the compound library.Results: Valaciclovir hydrochloride, Dihydrocapsaicin, Guanosine, Santacruzamate A, and 2'-Deoxyguanosine monohydrate compounds exhibited strong interactions with HDAC2. These compounds had a higher binding energy than the control compound, and they have promising drug-like properties and ADMET characteristics.Conclusion: These identified compounds could be used as HDAC2 inhibitors for the management of ASD, however, experimental research is needed to optimize them as HDAC2 inhibitors.Keywords: Autism spectrum disorder; Histone deacetylases; Alkaloid compounds; Drug-likeness

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Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor

Cited by 6 publications

References 29 publications

Fragment-to-Lead Medicinal Chemistry Publications in 2022

Fragment-to-Lead Medicinal Chemistry Publications in 2022

Medicinal chemistry advances in targeting class I histone deacetylases

In Silico Identification of Novel HDAC2 Inhibitors for Reinstating Synaptic wiring in Autism Spectrum Disorder

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