FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4200285750> ?p ?o ?g. }

• W4200285750 endingPage "P237" @default.
• W4200285750 startingPage "P237" @default.
• W4200285750 abstract "Abstract Cyclin-dependent kinase 9 (CDK9) is a master regulator of transcription that controls paused RNA polymerase II (RNAP2) release through phosphorylation of its carboxy-terminal domain, resulting in productive transcription elongation. CDK9 has been extensively studied as a potential target for cancer therapy in “transcriptionally addicted” tumors as transient inhibition of CDK9 primarily depletes proteins with short half-lives, such as the oncogenes MCL1 and MYC, making CDK9 a promising target in cancer. Here we show that PRT2527 is a potent and highly selective CDK9 inhibitor with moderate to high clearance that achieves optimal temporal target engagement and exhibits potent in vitro and in vivo activities. PRT2527 inhibited CDK9 enzymatic activity with an IC50 of 0.98 nM in a biochemical assay and showed high selectivity in a panel of kinases when tested at physiologically relevant 1 mM ATP concentration. In vitro, PRT2527 inhibited phosphorylation of Ser2RNAP2 in NCI-H929 cells with an IC50 of 54 nM, and an IC50 of 198 nM in a plasma assay to adjust for human plasma protein binding. Transient treatment of cells with PRT2527 inhibited pSer2RNAP2, depleted MCL1 and MYC proteins, and activated cleaved caspase-3 (CC3) in a concentration-dependent manner. In a proteomic profiling study, MCL1 was identified as one of the major down-regulated proteins following PRT2527 treatment. In a panel of hematological cancer cell lines representing B- and T-ALL, AML, and non-Hodgkin’s lymphoma (NHL), as well as subsets of sarcoma, prostate, adenoid cystic carcinoma (ACC), and non-small cell lung cancer (NSCLC) cell lines, PRT2527 treatment consistently led to a potent, concentration-dependent inhibition of proliferation. In a pharmacokinetic/pharmacodynamic (PK/PD) study, intravenous (IV) administration of PRT2527 achieved transient target engagement, depletion of MCL1 and MYC proteins, and induction of apoptosis in tumor tissue. This PK/PD correlation was successfully translated into in vivo efficacy in multiple models. Once weekly dosing of PRT2527 was well-tolerated and significantly inhibited tumor growth in various AML CDX models and induced tumor regressions in double-hit and triple-hit diffuse large B-cell lymphoma (DLBCL) CDX and PDX models carrying the MYC translocation. Combining PRT2527 with venetoclax achieved complete tumor regressions in a venetoclax resistant OCI-AML3 model. PRT2527 demonstrated potent ex vivo activity in PDX models of B-ALL and T-ALL, as well as various solid tumor PDX models with high levels of MYC amplification and overexpression, including pancreatic carcinoma, gastric and gastroesophageal carcinomas, NSCLC, and sarcoma. In vivo efficacy studies with once weekly IV administration of PRT2527 confirmed significant tumor growth inhibition in select MYC-amplified solid tumor PDX models. Taken together, this preclinical characterization supports the advancement of PRT2527 into clinical studies for transcriptionally addicted hematological malignancies and solid tumors with MYC amplification and/or dysregulation. Citation Format: Yang W. Zhang, Liang Lu, Min Wang, Dave Rominger, Stefan Ruepp, Kirsten Gallagher, William Gowen-MacDonald, Chaofeng Dai, Miles Cowart, Andrew Combs, Bruce Ruggeri, Peggy Scherle, Kris Vaddi. PRT2527 is a potent and selective CDK9 inhibitor that demonstrates anti-cancer activity in preclinical models of hematological malignancies and solid tumors with MYC amplification [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P237." @default.
• W4200285750 created "2021-12-31" @default.
• W4200285750 creator A5003146645 @default.
• W4200285750 creator A5013164569 @default.
• W4200285750 creator A5015102287 @default.
• W4200285750 creator A5018193992 @default.
• W4200285750 creator A5022438790 @default.
• W4200285750 creator A5024207488 @default.
• W4200285750 creator A5028111504 @default.
• W4200285750 creator A5034085965 @default.
• W4200285750 creator A5046355139 @default.
• W4200285750 creator A5048703920 @default.
• W4200285750 creator A5062211526 @default.
• W4200285750 creator A5084983321 @default.
• W4200285750 creator A5082918002 @default.
• W4200285750 date "2021-12-01" @default.
• W4200285750 modified "2023-09-25" @default.
• W4200285750 title "Abstract P237: PRT2527 is a potent and selective CDK9 inhibitor that demonstrates anti-cancer activity in preclinical models of hematological malignancies and solid tumors with <i>MYC</i> amplification" @default.
• W4200285750 doi "https://doi.org/10.1158/1535-7163.targ-21-p237" @default.
• W4200285750 hasPublicationYear "2021" @default.
• W4200285750 type Work @default.
• W4200285750 citedByCount "1" @default.
• W4200285750 countsByYear W42002857502023 @default.
• W4200285750 crossrefType "journal-article" @default.
• W4200285750 hasAuthorship W4200285750A5003146645 @default.
• W4200285750 hasAuthorship W4200285750A5013164569 @default.
• W4200285750 hasAuthorship W4200285750A5015102287 @default.
• W4200285750 hasAuthorship W4200285750A5018193992 @default.
• W4200285750 hasAuthorship W4200285750A5022438790 @default.
• W4200285750 hasAuthorship W4200285750A5024207488 @default.
• W4200285750 hasAuthorship W4200285750A5028111504 @default.
• W4200285750 hasAuthorship W4200285750A5034085965 @default.
• W4200285750 hasAuthorship W4200285750A5046355139 @default.
• W4200285750 hasAuthorship W4200285750A5048703920 @default.
• W4200285750 hasAuthorship W4200285750A5062211526 @default.
• W4200285750 hasAuthorship W4200285750A5082918002 @default.
• W4200285750 hasAuthorship W4200285750A5084983321 @default.
• W4200285750 hasConcept C121608353 @default.
• W4200285750 hasConcept C150903083 @default.
• W4200285750 hasConcept C153911025 @default.
• W4200285750 hasConcept C184235292 @default.
• W4200285750 hasConcept C185592680 @default.
• W4200285750 hasConcept C202751555 @default.
• W4200285750 hasConcept C207001950 @default.
• W4200285750 hasConcept C502942594 @default.
• W4200285750 hasConcept C54355233 @default.
• W4200285750 hasConcept C55493867 @default.
• W4200285750 hasConcept C59143045 @default.
• W4200285750 hasConcept C82495950 @default.
• W4200285750 hasConcept C86803240 @default.
• W4200285750 hasConcept C96232424 @default.
• W4200285750 hasConcept C97029542 @default.
• W4200285750 hasConceptScore W4200285750C121608353 @default.
• W4200285750 hasConceptScore W4200285750C150903083 @default.
• W4200285750 hasConceptScore W4200285750C153911025 @default.
• W4200285750 hasConceptScore W4200285750C184235292 @default.
• W4200285750 hasConceptScore W4200285750C185592680 @default.
• W4200285750 hasConceptScore W4200285750C202751555 @default.
• W4200285750 hasConceptScore W4200285750C207001950 @default.
• W4200285750 hasConceptScore W4200285750C502942594 @default.
• W4200285750 hasConceptScore W4200285750C54355233 @default.
• W4200285750 hasConceptScore W4200285750C55493867 @default.
• W4200285750 hasConceptScore W4200285750C59143045 @default.
• W4200285750 hasConceptScore W4200285750C82495950 @default.
• W4200285750 hasConceptScore W4200285750C86803240 @default.
• W4200285750 hasConceptScore W4200285750C96232424 @default.
• W4200285750 hasConceptScore W4200285750C97029542 @default.
• W4200285750 hasIssue "12_Supplement" @default.
• W4200285750 hasLocation W42002857501 @default.
• W4200285750 hasOpenAccess W4200285750 @default.
• W4200285750 hasPrimaryLocation W42002857501 @default.
• W4200285750 hasRelatedWork W2034251995 @default.
• W4200285750 hasRelatedWork W2339808165 @default.
• W4200285750 hasRelatedWork W2344637265 @default.
• W4200285750 hasRelatedWork W2386538333 @default.
• W4200285750 hasRelatedWork W2783732652 @default.
• W4200285750 hasRelatedWork W2902750284 @default.
• W4200285750 hasRelatedWork W2974647127 @default.
• W4200285750 hasRelatedWork W3011804615 @default.
• W4200285750 hasRelatedWork W3049178086 @default.
• W4200285750 hasRelatedWork W3215939181 @default.
• W4200285750 hasVolume "20" @default.
• W4200285750 isParatext "false" @default.
• W4200285750 isRetracted "false" @default.
• W4200285750 workType "article" @default.