Discovery of Pyrrolo[2,3-d]pyrimidine derivatives as potent and selective colony stimulating factor 1 receptor kinase inhibitors

Liang, Xiaofei; Wang, Chun; Wang, Beilei; Liu, Juan; Qi, Shuang; Wang, Aoli; Liu, Qingwang; Deng, Maoqing; Wang, Li; Liu, Jing; Liu, Qingsong

doi:10.1016/j.ejmech.2022.114782

Cited by 9 publications

(2 citation statements)

References 26 publications

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“…Compound 20 exhibited excellent activity against colony‐stimulating factor 1 receptor kinase (CSF1R, IC 50 : 5.14 nM) and BaF3‐TEL‐CSF1R, M‐NFS‐60 as well as BAF3‐TEL‐cKIT cancer cell lines (the concentration exhibiting 50% growth inhibition/GI 50 : 36–780 nM, Cell Titer‐Glo assay) and could inhibit the phosphorylation of CSF1R and its downstream signaling pathway. [ 34 ] In the M‐NFS‐60 xenografted mice model, compound 20 (100 mg/kg, oral administration) suppressed 51.8% tumor growth without affecting body weight, and the in vivo efficacy was comparable to that of pexidartinib (TGI: 50% at a dose of 50 mg/kg by oral administration). In addition, compound 20 (10 mg/kg, oral administration) also possessed acceptable pharmacokinetic properties with t 1/2 of 4.8 h, C max of 1193 ng/mL, AUC 0‐∞ of 14576 ng•h/mL, and bioavailability of 111%.…”

Section: Pyrrolo[23‐d]pyrimidine/pyrrolo[32‐d]pyrimidine Derivativesmentioning

confidence: 99%

Current scenario of fused pyrimidines with in vivo anticancer therapeutic potential

Xu,

Wang,

2024

Archiv der Pharmazie

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Cancer, characterized by uncontrolled cell growth and metastasis, is responsible for nearly one in six deaths and represents a severe threat to public health worldwide. Chemotherapy can substantially improve the quality of life and survival of patients with cancer, but anticancer chemotherapeutics are associated with a range of adverse effects. Moreover, almost all currently available anticancer chemotherapeutics could develop drug resistance over a period of time of application in cancer patients and ultimately lead to cancer relapse and death in 90% of patients, creating an urgent need to develop new anticancer agents. Fused pyrimidines trait the inextricable part of DNA and RNA and are vital in numerous biological processes. Fused pyrimidines can act on various biological cancer targets and have the potential to address drug resistance. In addition, more than 20 fused pyrimidines have already been approved for clinical treatment of different cancers and occupy a prominent place in the current therapeutic arsenal, revealing that fused pyrimidines are privileged scaffolds for the development of novel anticancer chemotherapeutics. The purpose of this review is to summarize the current scenario of fused pyrimidines with in vivo anticancer therapeutic potential along with their acute toxicity, metabolic profiles as well as pharmacokinetic properties, toxicity and mechanisms of action developed from 2020 to the present to facilitate further rational exploitation of more effective candidates.

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Section: Pyrrolo[23‐d]pyrimidine/pyrrolo[32‐d]pyrimidine Derivativesmentioning

confidence: 99%

Current scenario of fused pyrimidines with in vivo anticancer therapeutic potential

Xu,

Wang,

2024

Archiv der Pharmazie

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“…Compound 28 has been identified as a potent and selective CSF1R inhibitor, with an IC 50 value of 5.1 nM against CSF1R. Notably, it exhibits significant selectivity over other type III receptor tyrosine kinases, showing more than a 38‐fold greater binding preference [72]. Through a combination of medicinal chemistry guided structure–activity relationships and structure‐based drug design, Deciphera Inc. successfully identified a novel series of potent acyl urea‐based CSF1R inhibitors.…”

Section: Recent New Csf1r Ligandsmentioning

confidence: 99%

Targeting colony‐stimulating factor 1 receptor: From therapeutic drugs to diagnostic radiotracers

Zha,

Hui,

Cheng

et al. 2023

iRADIOLOGY

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Colony‐stimulating factor 1 receptor (CSF1R) is highly expressed in mononuclear phagocytes and in the central nervous system. It has emerged as a promising target for tumor therapy and neuroinflammation imaging. Although therapeutic agents targeting CSF1R have shown great success, the development of diagnostic radiotracers for CSF1R has faced numerous challenges. Consequently, there is an urgent need to overcome these obstacles for the development of CSF1R radiotracers, particularly positron emission tomography tracers, not only for diagnostic purposes but also to aid the development of more effective therapeutic drugs. Here, we provide a comprehensive overview of the development of CSF1R radiotracers, presenting detailed profiles of each tracer's ability to image CSF1R. Additionally, we discuss reported CSF1R small‐molecule inhibitors and antibodies, highlighting their relevance to the further development of CSF1R radiotracers. We aim to shed light on the current state of CSF1R radiotracer research and development, provide an insight into the challenges in this field, and offer guidance for future exploration.

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Pyrrolo[2,3-d]pyrimidines as potential kinase inhibitors in cancer drug discovery: A critical review

Sai Madhurya,

Thakur,

Dastari

et al. 2024

Bioorganic Chemistry

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Discovery of Pyrrolo[2,3-d]pyrimidine derivatives as potent and selective colony stimulating factor 1 receptor kinase inhibitors

Cited by 9 publications

References 26 publications

Current scenario of fused pyrimidines with in vivo anticancer therapeutic potential

Current scenario of fused pyrimidines with in vivo anticancer therapeutic potential

Targeting colony‐stimulating factor 1 receptor: From therapeutic drugs to diagnostic radiotracers

Pyrrolo[2,3-d]pyrimidines as potential kinase inhibitors in cancer drug discovery: A critical review

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