Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives

Fang, Yuan; Liao, Guochao; Yu, Bin

doi:10.1016/j.apsb.2020.01.003

Cited by 74 publications

(64 citation statements)

References 127 publications

(145 reference statements)

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“…At present, PROTAC technology has been extensively used in drug development 121 , 122 , 123 , but TRK PROTACs have been rarely reported. The strategy of TRKC degradation is shown in Fig.…”

Section: Trk Inhibitors and Their Therapeutic Implicationsmentioning

confidence: 99%

Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers

Jiang

Wang

Liu

et al. 2021

Acta Pharmaceutica Sinica B

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Tropomyosin receptor kinase A, B and C (TRKA, TRKB and TRKC), which are well-known members of the cell surface receptor tyrosine kinase (RTK) family, are encoded by the neurotrophic receptor tyrosine kinase 1, 2 and 3 ( NTRK1, NTRK2 and NTRK3 ) genes, respectively. TRKs can regulate cell proliferation, differentiation and even apoptosis through the RAS/MAPKs, PI3K/AKT and PLC γ pathways. Gene fusions involving NTRK act as oncogenic drivers of a broad diversity of adult and pediatric tumors, and TRKs have become promising antitumor targets. Therefore, achieving a comprehensive understanding of TRKs and relevant TRK inhibitors should be urgently pursued for the further development of novel TRK inhibitors for potential clinical applications. This review focuses on summarizing the biological functions of TRKs and NTRK fusion proteins, the development of small-molecule TRK inhibitors with different chemotypes and their activity and selectivity, and the potential therapeutic applications of these inhibitors for future cancer drug discovery efforts.

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“…At present, PROTAC technology has been extensively used in drug development 121 , 122 , 123 , but TRK PROTACs have been rarely reported. The strategy of TRKC degradation is shown in Fig.…”

Section: Trk Inhibitors and Their Therapeutic Implicationsmentioning

confidence: 99%

Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers

Jiang

Wang

Liu

et al. 2021

Acta Pharmaceutica Sinica B

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“…Recent efforts have identified more soluble and potent MDM2-p53 PPI inhibitors that may increase the use of MDM2 future TPD efforts. 83 Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)dependent Protein Erasers (SNIPERs) are a TPD technology that recruits the cellular inhibitor of apoptosis protein (cIAP) using methyl bestatin analogs. 84 These molecules are said to be distinct from PROTACs because SNIPERs induce the degradation of both the E3 ligase cIAP and the POI.…”

Section: Synergistic E3res -Mdm2 Ciap and Ahrmentioning

confidence: 99%

Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation

2021

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“…Small molecule inhibitors such as nutlins and di-hydroisoquinolinones can disrupt the binding of MDM2 to p53, and their use has induced positive response in tumors retaining wild-type p53. Some of these compounds have entered clinical trials [ 249 ].…”

Section: Why Do We Need To Identify Novel Molecular Perturbations?mentioning

confidence: 99%

Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial Treatments, and New Developments

Yip

Papa

2021

Cells

147

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Molecular alterations in cancer genes and associated signaling pathways are used to inform new treatments for precision medicine in cancer. Small molecule inhibitors and monoclonal antibodies directed at relevant cancer-related proteins have been instrumental in delivering successful treatments of some blood malignancies (e.g., imatinib with chronic myelogenous leukemia (CML)) and solid tumors (e.g., tamoxifen with ER positive breast cancer and trastuzumab for HER2-positive breast cancer). However, inherent limitations such as drug toxicity, as well as acquisition of de novo or acquired mechanisms of resistance, still cause treatment failure. Here we provide an up-to-date review of the successes and limitations of current targeted therapies for cancer treatment and highlight how recent technological advances have provided a new level of understanding of the molecular complexity underpinning resistance to cancer therapies. We also raise three basic questions concerning cancer drug discovery based on molecular markers and alterations of selected signaling pathways, and further discuss how combination therapies may become the preferable approach over monotherapy for cancer treatments. Finally, we consider novel therapeutic developments that may complement drug delivery and significantly improve clinical response and outcomes of cancer patients.

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Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives

Cited by 74 publications

References 127 publications

Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers

Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers

Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation

Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial Treatments, and New Developments

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