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

Abstract

Blocking the MDM2/X–P53 protein–protein interaction has been widely recognized as an attractive therapeutic strategy for the treatment of cancers. Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2–P53 interaction in 1996, SAR405838, NVP-CGM097, MK-8242, RG7112, RG7388, DS-3032b, and AMG232 currently undergo clinical evaluation for cancer therapy. This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera (PROTAC) degraders with a particular focus on how these inhibitors or degraders are identified from starting points, strategies employed, structure–activity relationship (SAR) studies, binding modes or co-crystal structures, biochemical data, mechanistic studies, and preclinical/clinical studies. Moreover, we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition, acquired resistance and toxicity of P53 activation as well as future directions.

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

“…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.…”

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

“…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.…”

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

“…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 ].…”