755039-56-6Relevant academic research and scientific papers
Compound containing methotrexate structure as well as preparation method and application thereof
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Paragraph 0071; 0083-0084, (2021/11/14)
The invention discloses a compound of a general formula (I) containing a tetrahydrotrexate structure and a preparation method and application thereof. The invention also discloses a composition containing the methotrexate compound or a pharmaceutically ac
Discovery of Potent and Novel Dual PARP/BRD4 Inhibitors for Efficient Treatment of Pancreatic Cancer
Gao, Ling-Li,Huang, Lei,Huang, Shi-Hui,Li, Yu,Lin, Qian-Wen,Meng, Liu-Qiong,Sun, Qin,Wang, Shu-Ping,Wu, Shi-Qi,Xu, Yun-Gen,Zhu, Qi-Hua,Zou, Yi
, p. 17413 - 17435 (2021/12/06)
Targeting poly(ADP-ribose) polymerase1/2 (PARP1/2) is a promising strategy for the treatment of pancreatic cancer with breast cancer susceptibility gene (BRCA) mutation. Inducing the deficiency of homologous recombination (HR) repair is an effective way t
Dual Inhibition of TAF1 and BET Bromodomains from the BI-2536 Kinase Inhibitor Scaffold
Remillard, David,Buckley, Dennis L.,Seo, Hyuk-Soo,Ferguson, Fleur M.,Dhe-Paganon, Sirano,Bradner, James E.,Gray, Nathanael S.
supporting information, p. 1443 - 1449 (2019/10/11)
Recent reports have highlighted the dual bromodomains of TAF1 (TAF1(1,2)) as synergistic with BET inhibition in cellular cancer models, engendering interest in TAF/BET polypharmacology. Here, we examine structure activity relationships within the BI-2536 PLK1 kinase inhibitor scaffold, previously reported to bind BRD4. We examine binding by this ligand to TAF1(2) and apply structure guided design strategies to discriminate binding to both the PLK1 kinase and BRD4(1) bromodomain while retaining activity on TAF1(2). Through this effort we discover potent dual inhibitors of TAF1(2)/BRD4(1), as well as biased derivatives showing marked TAF1 selectivity. We resolve X-ray crystallographic data sets to examine the mechanisms of the observed TAF1 selectivity and to provide a resource for further development of this scaffold.
Structure-Guided Design and Development of Potent and Selective Dual Bromodomain 4 (BRD4)/Polo-like Kinase 1 (PLK1) Inhibitors
Liu, Shuai,Yosief, Hailemichael O.,Dai, Lingling,Huang, He,Dhawan, Gagan,Zhang, Xiaofeng,Muthengi, Alex M.,Roberts, Justin,Buckley, Dennis L.,Perry, Jennifer A.,Wu, Lei,Bradner, James E.,Qi, Jun,Zhang, Wei
, p. 7785 - 7795 (2018/09/13)
The simultaneous inhibition of polo-like kinase 1 (PLK1) and BRD4 bromodomain by a single molecule could lead to the development of an effective therapeutic strategy for a variety of diseases in which PLK1 and BRD4 are implicated. Compound 23 has been found to be a potent dual kinase-bromodomain inhibitor (BRD4-BD1 IC50 = 28 nM, PLK1 IC50 = 40 nM). Compound 6 was found to be the most selective PLK1 inhibitor over BRD4 in our series (BRD4-BD1 IC50 = 2579 nM, PLK1 IC50 = 9.9 nM). Molecular docking studies with 23 and BRD4-BD1/PLK1 as well as with 6 corroborate the biochemical assay results.
REGULATING CHIMERIC ANTIGEN RECEPTORS
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Page/Page column 323; 324, (2018/09/08)
This invention is in the area of compositions and methods for regulating chimeric antigen receptor immune effector cell, for example T-cell (CAR-T), therapy to modulate associated adverse inflammatory responses, for example, cytokine release syndrome and tumor lysis syndrome, using targeted protein degradation.
TUNABLE ENDOGENOUS PROTEIN DEGRADATION WITH HETEROBIFUNCTIONAL COMPOUNDS
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Page/Page column 305, (2018/09/08)
The present invention provides a means to modulate gene expression in vivo in a manner that avoids problems associated with CRISPR endogenous protein knock-out or knock-in strategies and strategies that provide for correction, or alteration, of single nucleotides. The invention includes inserting into the genome a nucleotide encoding a heterobifunctional compound targeting protein (dTAG) in-frame with the nucleotide sequence of a gene encoding an endogenously expressed protein of interest which, upon expression, produces an endogenous protein-dTAG hybrid protein. This allows for targeted protein degradation of the dTAG and the fused endogenous protein using a heterobifunctional compound.
METHODS TO INDUCE TARGETED PROTEIN DEGRADATION THROUGH BIFUNCTIONAL MOLECULES
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Page/Page column 245-246, (2017/02/28)
The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to nucleic acids, polypeptides, cells, and methods for highly regulated, targeted degradation of proteins through the use of the bifunctional compounds.
Development of Bifunctional Inhibitors of Polo-Like Kinase 1 with Low-Nanomolar Activities Against the Polo-Box Domain
Scharow, Andrej,Knappe, Daniel,Reindl, Wolfgang,Hoffmann, Ralf,Berg, Thorsten
, p. 759 - 767 (2016/04/26)
Polo-like kinase 1 (Plk1), a validated cancer target, harbors a protein-protein interaction domain referred to as the polo-box domain (PBD), in addition to its enzymatic domain. Although functional inhibition either of the enzymatic domain or of the PBD has been shown to inhibit Plk1, so far there have been no reports of bifunctional agents with the potential to target both protein domains. Here we report the development of Plk1 inhibitors that incorporate both an ATP-competitive ligand of the enzymatic domain, derived from BI 2536, and a functional inhibitor of the PBD, based either on the small molecule poloxin-2 or on a PBD-binding peptide. Although these bifunctional agents do not seem to bind both protein domains simultaneously, the most potent compound displays low-nanomolar activity against the Plk1 PBD, with excellent selectivity over the PBDs of Plk2 and Plk3. Our data provide insights into challenges and opportunities relating to the optimization of Plk1 PBD ligands as potent Plk1 inhibitors.
METHODS TO INDUCE TARGETED PROTEIN DEGRADATION THROUGH BIFUNCTIONAL MOLECULES
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Paragraph 0628; 0631-0632, (2016/07/27)
The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of proliferative disorders. The present application also provides methods for making compounds of the application and intermediates thereof.
Bioorthogonal probes for polo-like kinase 1 imaging and quantification
Budin, Ghyslain,Yang, Katherine S.,Reiner, Thomas,Weissleder, Ralph
supporting information; experimental part, p. 9378 - 9381 (2011/11/07)
Click inside: A nuclear protein target, polo-like kinase 1 (PLK1) was imaged using a biocompatible bioorthogonal ligation between a specific drug and a fluorescent dye in live cells (see picture). Colocalization of the dye and the protein target was confi
