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Sun D , Nikonova AS , Zhang P , Deneka AY , Fitzgerald ME , Michael RE , Lee L , Lilly AC , Fisher SL , Phillips AJ , Nasveschuk CG , Proia DA , Tu Z , Golemis EA
Evaluation of the small-molecule BRD4-degrader CFT-2718 in small cell lung cancer and pancreatic cancer models
Mol Cancer Ther. 2021 Aug;20(8) :1367-1377
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Abstract
Targeted, catalytic degradation of oncoproteins using heterobifunctional small molecules is an attractive modality, particularly for hematological malignancies which are often initiated by aberrant transcription factors and are challenging to drug with inhibitors. BRD4, a member of the Bromodomain and Extraterminal (BET) family, is a core transcriptional and epigenetic regulator that recruits the P-TEFb complex, which includes Cdk9 and cyclin T, to RNA polymerase II (pol II). Together, BRD4 and CDK9 phosphorylate serine 2 (pSer2) of heptad repeats in the C-terminal domain of RPB1, the large subunit of pol II, promoting transcriptional elongation. Small molecule degraders of BRD4 have shown encouraging efficacy in preclinical models for several tumor types, but less efficacy in other cancers including small cell lung cancer (SCLC) and pancreatic cancer. We here evaluated CFT-2718, a new BRD4-targeting degrader with enhanced catalytic activity and in vivo properties. In vivo, CFT-2718 has significantly greater efficacy than the CDK9 inhibitor dinaciclib in reducing growth of the LX-36 SCLC patient-derived xenograft (PDX) model and performed comparably to dinaciclib in limiting growth of the PNX-001 pancreatic PDX model. In vitro, CFT-2718 reduced cell viability in four SCLC and two pancreatic cancer models. In SCLC models, this activity significantly exceeded that of dinaciclib; further, CFT-2718 selectively increased the expression of cleaved Poly (ADP-ribose) polymerase PARP, an indicator of apoptosis. CFT-2718 caused rapid BRD4 degradation and reduced levels of total and pSer2 RPB1 protein. These and other findings suggest that BRD-mediated transcriptional suppression merits further exploration in the setting of SCLC.
Notes
1538-8514 Sun, Danlin Nikonova, Anna S Zhang, Peishan Orcid: 0000-0002-8863-9962 Deneka, Alexander Y Fitzgerald, Mark E Michael, Ryan E Lee, Linda Lilly, Anna C Fisher, Stewart L Phillips, Andrew J Nasveschuk, Christopher G Proia, David A Tu, Zhigang Golemis, Erica A Orcid: 0000-0003-3618-3673 Journal Article United States Mol Cancer Ther. 2021 May 27:molcanther.0831.2020. doi: 10.1158/1535-7163.MCT-20-0831.