2244520-92-9Relevant articles and documents
Mutant-Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug-Resistant Mutations
De Clercq, Dries J. H.,Eck, Michael J.,Fischer, Eric S.,Gray, Nathanael S.,J?nne, Pasi A.,Jang, Jaebong,Mushajiang, Mierzhati,Nowak, Rados?aw P.,Park, Eunyoung,Ponthier, Charles M.,Shin, Bo Hee,To, Ciric
, p. 14481 - 14489 (2020)
Targeting epidermal growth factor receptor (EGFR) through an allosteric mechanism provides a potential therapeutic strategy to overcome drug-resistant EGFR mutations that emerge within the ATP binding site. Here, we develop an allosteric EGFR degrader, DDC-01-163, which can selectively inhibit the proliferation of L858R/T790M (L/T) mutant Ba/F3 cells while leaving wildtype EGFR Ba/F3 cells unaffected. DDC-01-163 is also effective against osimertinib-resistant cells with L/T/C797S and L/T/L718Q EGFR mutations. When combined with an ATP-site EGFR inhibitor, osimertinib, the anti-proliferative activity of DDC-01-163 against L858R/T790M EGFR-Ba/F3 cells is enhanced. Collectively, DDC-01-163 is a promising allosteric EGFR degrader with selective activity against various clinically relevant EGFR mutants as a single agent and when combined with an ATP-site inhibitor. Our data suggests that targeted protein degradation is a promising drug development approach for mutant EGFR.
Discovery of a Napabucasin PROTAC as an Effective Degrader of the E3 Ligase ZFP91
Hanafi, Maha,Chen, Xinde,Neamati, Nouri
, p. 1626 - 1648 (2021/02/27)
Napabucasin, undergoing multiple clinical trials, was reported to inhibit the signal transducer and transcription factor 3 (STAT3). To better elucidate its mechanism of action, we designed a napabucasin-based proteolysis targeting chimera (PROTAC), XD2-149 that resulted in inhibition of STAT3 signaling in pancreatic cancer cell lines without inducing proteasome-dependent degradation of STAT3. Proteomics analysis of XD2-149 revealed the downregulation of the E3 ubiquitin-protein ligase ZFP91. XD2-149 degrades ZFP91 with DC50 values in the nanomolar range. The cytotoxicity of XD2-149 was significantly, but not fully, reduced with ZFP91 knockdown providing evidence for its multi-targeted mechanism of action. The NQO1 inhibitor, dicoumarol, rescued the cytotoxicity of XD2-149 but not ZFP91 degradation, suggesting that the NQO1-induced cell death is independent of ZFP91. ZFP91 plays a role in tumorigenesis and is involved in multiple oncogenic pathways including NF-κB and HIF-1α.
Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti-Proliferative Activity in Lung Cancer Cells
Chen, Deng,Cool, Robbert H.,Dekker, Frank J.,Melgert, Barbro N.,Poelarends, Gerrit J.,Quax, Wim J.,Song, Shanshan,Xiao, Zhangping,van Merkerk, Ronald,van der Wouden, Petra E.
, p. 17514 - 17521 (2021/07/02)
Macrophage migration inhibitory factor (MIF) is involved in protein-protein interactions that play key roles in inflammation and cancer. Current strategies to develop small molecule modulators of MIF functions are mainly restricted to the MIF tautomerase active site. Here, we use this site to develop proteolysis targeting chimera (PROTAC) in order to eliminate MIF from its protein-protein interaction network. We report the first potent MIF-directed PROTAC, denoted MD13, which induced almost complete MIF degradation at low micromolar concentrations with a DC50 around 100 nM in A549 cells. MD13 suppresses the proliferation of A549 cells, which can be explained by deactivation of the MAPK pathway and subsequent induction of cell cycle arrest at the G2/M phase. MD13 also exhibits antiproliferative effect in a 3D tumor spheroid model. In conclusion, we describe the first MIF-directed PROTAC (MD13) as a research tool, which also demonstrates the potential of PROTACs in cancer therapy.
Dihydropyrimidine-pomalidomide conjugate as well as preparation method and application thereof
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Paragraph 0050-0051; 0055-0057, (2021/10/20)
The invention provides a dihydropyrimidine-pomalidomide conjugate as well as a preparation method and application thereof. The conjugate has a structure as shown in a formula I. The invention further relates to a preparation method of the compound with the structure as shown in the formula I, a pharmaceutical composition and application of the compound in preparation of anti-HBV drugs.
