Macrocyclization strategy for improving candidate profiles in medicinal chemistry

Darlami, Om; Pun, Rabin; Ahn, Sung-Hoon; Kim, Seok-Ho; Shin, Dongyun

doi:10.1016/j.ejmech.2024.116501

European Journal of Medicinal Chemistry

2024

DOI: 10.1016/j.ejmech.2024.116501

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Macrocyclization strategy for improving candidate profiles in medicinal chemistry

Om Darlami,

Rabin Pun,

Sung-Hoon Ahn

et al.

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2024

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Cited by 3 publications

References 187 publications

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Macrocyclic-based strategy in drug design: From lab to the clinic

Jin,

Ding,

Guo

et al. 2024

European Journal of Medicinal Chemistry

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Macrocyclic-based strategy in drug design: From lab to the clinic

Jin,

Ding,

Guo

et al. 2024

European Journal of Medicinal Chemistry

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Discovery of a Novel Macrocyclic Noncovalent CDK7 Inhibitor for Cancer Therapy

Lu,

Zhang,

Liu

et al. 2024

J. Med. Chem.

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Cyclin-dependent kinase 7 (CDK7) is a key regulator of the cell cycle and transcription, making it a promising target for cancer therapy. Although current CDK7 inhibitors have improved in their selectivity and druglike properties, CDK7 inhibitors have failed to progress through clinical development due to severe gastrointestinal and hematotoxic side effects. To mitigate these limitations, we have developed novel, macrocyclic, noncovalent CDK7 hit compounds 2 and 3 using a macrocyclization platform that has optimized these compounds from SY-5609, a leading clinical asset. We conducted extensive structure−activity relationship (SAR) studies to improve their potency, enhance oral bioavailability, and reduce intestinal distribution, which resulted in compound 13. Compound 13 exhibits potent in vitro activity, good ADME properties, and robust in vivo antitumor activity in xenograft models as a monotherapy. Notably, compound 13 with lower basicity demonstrated improved Caco-2 permeability, reduced blood/plasma ratio, and reduced intestinal distribution in rats, thus mitigating gastrointestinal and hematotoxic side effects.

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Remodeling of tumour microenvironment: strategies to overcome therapeutic resistance and innovate immunoengineering in triple-negative breast cancer

Singh,

Haque,

Kim

et al. 2024

Front. Immunol.

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Triple-negative breast cancer (TNBC) stands as the most complex and daunting subtype of breast cancer affecting women globally. Regrettably, treatment options for TNBC remain limited due to its clinical complexity. However, immunotherapy has emerged as a promising avenue, showing success in developing effective therapies for advanced cases and improving patient outcomes. Improving TNBC treatments involves reducing side effects, minimizing systemic toxicity, and enhancing efficacy. Unlike traditional cancer immunotherapy, engineered nonmaterial’s can precisely target TNBC, facilitating immune cell access, improving antigen presentation, and triggering lasting immune responses. Nanocarriers with enhanced sensitivity and specificity, specific cellular absorption, and low toxicity are gaining attention. Nanotechnology-driven immunoengineering strategies focus on targeted delivery systems using multifunctional molecules for precise tracking, diagnosis, and therapy in TNBC. This study delves into TNBC’s tumour microenvironment (TME) remodeling, therapeutic resistance, and immunoengineering strategies using nanotechnology.

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Macrocyclization strategy for improving candidate profiles in medicinal chemistry

Cited by 3 publications

References 187 publications

Macrocyclic-based strategy in drug design: From lab to the clinic

Macrocyclic-based strategy in drug design: From lab to the clinic

Discovery of a Novel Macrocyclic Noncovalent CDK7 Inhibitor for Cancer Therapy

Remodeling of tumour microenvironment: strategies to overcome therapeutic resistance and innovate immunoengineering in triple-negative breast cancer

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