Novel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancers

Kuchukulla, Ratnakar Reddy; Hwang, Injeoung; Park, Sang Won; Moon, Sojeong; Kim, Suhn Hyung; Kim, Sumin; Chung, Hwan Won; Ji, Mi‐Jung; Park, Hyun-Mee; Hur, Wooyoung

doi:10.3390/ph15091041

Cited by 6 publications

(3 citation statements)

References 34 publications

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“…Docking analysis of compounds against NSD3 was carried out following the method used previously (Kuchukulla et al, 2022). Using the crystal structure of SAM‐bound human NSD3 SET domain (pdb id: 6cen) (Morrison et al, 2018), the receptor structure was generated after elimination of water molecules and the processing steps for missing or abnormal residues.…”

Section: Methodsmentioning

confidence: 99%

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Identification of novel class inhibitors of NSD3 methyltransferase showing a unique, bivalent binding mode in the SET domain

et al. 2023

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NSD3/WHSC1L1 lysine methyltransferase promotes the transcription of target genes through di‐ or tri‐methylation at histone H3K36 using SAM as a cofactor. Genetic alterations such as amplification and gain‐of‐function mutation of NSD3 act as oncogenic drivers in several cancers including squamous cell lung cancer and breast cancer. NSD3 is an important therapeutic target for cancers, but the reported NSD3 inhibitors targeting the catalytic SET domain are very rare and show a poor activity. Herein, from a virtual library screening and the subsequent medicinal chemistry optimization, we identified a novel class of NSD3 inhibitors. Our docking analysis and pulldown result suggested that the most potent analogue 13i shows a unique, bivalent binding mode interacting with both SAM‐binding site and BT3‐bindig site within the SET domain. We found 13i inhibits NSD3 activity with IC50 = 287 μM in vitro and suppresses the proliferation of JIMT1 breast cancer cells with GI50 = 36.5 μM, which express a high level of NSD3. Also, 13i downregulated the levels of H3K36me2/3 in a dose‐dependent manner. Our study could provide an insight in designing high‐affinity NSD3 inhibitors. Also, as the acrylamide group of 13i was predicted to position near Cys1265 in the BT3‐binding site, further optimization would lead to a discovery of novel irreversible NSD3 inhibitors.

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Section: Methodsmentioning

confidence: 99%

“…Anti-proliferative assays using JIMT1 cells (5000 cells/ well) were performed as reported previously (Kuchukulla et al, 2022).…”

Section: Antiproliferation Assaymentioning

confidence: 99%

Identification of novel class inhibitors of NSD3 methyltransferase showing a unique, bivalent binding mode in the SET domain

et al. 2023

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“…Recently, chemically distinct compounds have been found to degrade cyclin K (refs. 8 , 10 , 11 , 20 , 21 ), but as several lack any obvious chemical similarity to CR8 (refs. 8 , 10 , 11 ), their precise mode of action remained unknown.…”

Section: Mainmentioning

confidence: 99%

Design principles for cyclin K molecular glue degraders

Kozicka,

Suchyta,

Focht

et al. 2023

Nat Chem Biol

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Molecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12–cyclin K to the DDB1–CUL4–RBX1 E3 ligase. Here, to investigate how chemically dissimilar small molecules trigger cyclin K degradation, we evaluated 91 candidate degraders in structural, biophysical and cellular studies and reveal all compounds acquire glue activity via simultaneous CDK12 binding and engagement of DDB1 interfacial residues, in particular Arg928. While we identify multiple published kinase inhibitors as cryptic degraders, we also show that these glues do not require pronounced inhibitory properties for activity and that the relative degree of CDK12 inhibition versus cyclin K degradation is tuneable. We further demonstrate cyclin K degraders have transcriptional signatures distinct from CDK12 inhibitors, thereby offering unique therapeutic opportunities. The systematic structure–activity relationship analysis presented herein provides a conceptual framework for rational molecular glue design.

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The anti‐breast cancer therapeutic potential of 1,2,3‐triazole‐containing hybrids

Song,

Zhang,

Zhang

et al. 2023

Archiv der Pharmazie

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Breast cancer, as one of the most common invasive malignancies and the leading cause of cancer‐related deaths in women globally, poses a significant challenge in the world health system. Substantial advances in diagnosis and treatment have significantly improved the survival rate of breast cancer patients, but the number of incidences and deaths of breast cancer are projected to increase by 40% and 50%, respectively, by 2040. Chemotherapy is one of the principal treatments for breast cancer therapy, but multidrug resistance and severe side effects remain the major obstacles to the success of treatment. Hence, there is a vital need to develop novel chemotherapeutic agents to combat this deadly disease. 1,2,3‐Triazole, which can be effectively constructed by click chemistry, not only can serve as a linker to connect different anti‐breast cancer pharmacophores but also is a valuable pharmacophore with anti‐breast cancer potential and favorable properties such as hydrogen bonding, moderate dipole moment, and enhanced water solubility. Particularly, 1,2,3‐triazole‐containing hybrids have demonstrated promising in vitro and in vivo anti‐breast cancer potential against both drug‐sensitive and drug‐resistant forms and possessed excellent selectivity by targeting different biological pathways associated with breast cancer, representing privileged scaffolds for the discovery of novel anti‐breast cancer candidates. This review concentrates on the latest advancements of 1,2,3‐triazole‐containing hybrids with anti‐breast cancer potential, including work published between 2020 and the present. The structure–activity relationships (SARs) and mechanisms of action are also reviewed to shed light on the development of more effective and multitargeted candidates.

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Novel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancers

Cited by 6 publications

References 34 publications

Identification of novel class inhibitors of NSD3 methyltransferase showing a unique, bivalent binding mode in the SET domain

Identification of novel class inhibitors of NSD3 methyltransferase showing a unique, bivalent binding mode in the SET domain

Design principles for cyclin K molecular glue degraders

The anti‐breast cancer therapeutic potential of 1,2,3‐triazole‐containing hybrids

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