Small molecule inhibitors for cancer immunotherapy and associated biomarkers – the current status

Schlicher, Lisa; Green, Luke G.; Romagnani, Andrea; Renner, Florian

doi:10.3389/fimmu.2023.1297175

Cited by 5 publications

(1 citation statement)

References 212 publications

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“…In recent years, the concept of using small molecules to interfere with intracellular targets has emerged in both immunology and in immuno-oncology, as exemplified by JAK inhibitors for rheumatoid arthritis or orally available small molecule targeting sTNF (SAR441566) or inhibitors of various intracellular negative regulators of the antitumor immune response (MAP4K1, DGKα, EP4, ...), , ERAP enzymes involved in antigen presentation pathway, may become the target for small molecule drugs in immunology and immuno-oncology upstream of the current interventions.…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

ERAP Inhibitors in Autoimmunity and Immuno-Oncology: Medicinal Chemistry Insights

Fougiaxis,

He,

Khan

et al. 2024

J. Med. Chem.

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Endoplasmic reticulum aminopeptidases ERAP1 and 2 are intracellular aminopeptidases that trim antigenic precursors and generate antigens presented by major histocompatibility complex class I (MHC-I) molecules. They thus modulate the antigenic repertoire and drive the adaptive immune response. ERAPs are considered as emerging targets for precision immuno-oncology or for the treatment of autoimmune diseases, in particular MHC-I-opathies. This perspective covers the structural and biological characterization of ERAP, their relevance to these diseases and the ongoing research on small-molecule inhibitors. We describe the chemical and pharmacological space explored by medicinal chemists to exploit the potential of these targets given their localization, biological functions, and family depth. Specific emphasis is put on the binding mode, potency, selectivity, and physchem properties of inhibitors featuring diverse scaffolds. The discussion provides valuable insights for the future development of ERAP inhibitors and analysis of persisting challenges for the translation for clinical applications.

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Section: Discussion and Perspectivesmentioning

confidence: 99%

ERAP Inhibitors in Autoimmunity and Immuno-Oncology: Medicinal Chemistry Insights

Fougiaxis,

He,

Khan

et al. 2024

J. Med. Chem.

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Design, synthesis and structure-activity relationship of malonic acid non-nucleoside derivatives as potent CD73 inhibitors

Shi,

Dai,

Chang

et al. 2024

Bioorganic & Medicinal Chemistry Letters

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In Silico Insights: QSAR Modeling of TBK1 Kinase Inhibitors for Enhanced Drug Discovery

Ivanov,

Tenchov,

Ralhan

et al. 2024

J. Chem. Inf. Model.

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TBK1, or TANK-binding kinase 1, is an enzyme that functions as a serine/threonine protein kinase. It plays a crucial role in various cellular processes, including the innate immune response to viruses, cell proliferation, apoptosis, autophagy, and antitumor immunity. Dysregulation of TBK1 activity can lead to autoimmune diseases, neurodegenerative disorders, and cancer. Due to its central role in these critical pathways, TBK1 is a significant focus of research for therapeutic drug development. In this paper, we explore data from the CAS Content Collection regarding TBK1 and its implication in a large assortment of diseases and disorders. With the demand for developing efficient TBK1 inhibitors being outlined, we focus on utilizing a machine learning approach for developing predictive models for TBK1 inhibition, derived from the fragment-functional analysis descriptors. Using the extensive CAS Content Collection, we assembled a training set of TBK1 inhibitors with experimentally measured IC50 values. We explored several machine learning techniques combined with various molecular descriptors to derive and select the best TBK1 inhibitor QSAR models. Certain significant structural alerts that potentially contribute to inhibition of TBK1 are outlined and discussed. The merit of the article stems from identifying the most adequate TBK1 QSAR models and subsequent successful development of advanced positive training data to facilitate and enhance drug discovery for an important therapeutic target such as TBK1 inhibitors, based on an extensive, wide-ranging set of scientific information provided by the CAS Content Collection.

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Small molecule inhibitors for cancer immunotherapy and associated biomarkers – the current status

Cited by 5 publications

References 212 publications

ERAP Inhibitors in Autoimmunity and Immuno-Oncology: Medicinal Chemistry Insights

ERAP Inhibitors in Autoimmunity and Immuno-Oncology: Medicinal Chemistry Insights

Design, synthesis and structure-activity relationship of malonic acid non-nucleoside derivatives as potent CD73 inhibitors

In Silico Insights: QSAR Modeling of TBK1 Kinase Inhibitors for Enhanced Drug Discovery

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