153162-70-0Relevant academic research and scientific papers
RNA G-Quadruplexes in Kirsten Ras (KRAS) Oncogene as Targets for Small Molecules Inhibiting Translation
Miglietta, Giulia,Cogoi, Susanna,Marinello, Jessica,Capranico, Giovanni,Tikhomirov, Alexander S.,Shchekotikhin, Andrey,Xodo, Luigi E.
, p. 9448 - 9461 (2017)
The human KRAS transcript contains a G-rich 5′-UTR sequence (77% GC) harboring several G4 motifs capable to form stable RNA G-quadruplex (RG4) structures that can serve as targets for small molecules. A biotin-streptavidin pull-down assay showed that 4,11-bis(2-aminoethylamino)anthra[2,3-b]furan-5,10-dione (2a) binds to RG4s in the KRAS transcript under low-abundance cellular conditions. Dual-luciferase assays demonstrated that 2a and its analogue 4,11-bis(2-aminoethylamino)anthra[2,3-b]thiophene-5,10-dione (2b) repress translation in a dose-dependent manner. The effect of the G4-ligands on Panc-1 cancer cells has also been examined. Both 2a and 2b efficiently penetrate the cells, suppressing protein p21KRAS to a dramatic reduction of cell growth and colony formation. In summary, we report a strategy to suppress the KRAS oncogene in pancreatic cancer cells by means of small molecules binding to RG4s in the 5′-UTR of mRNA.
A new biotin derivative-DOTA conjugate as a candidate for pretargeted diagnosis and therapy of tumors
Sabatino, Giuseppina,Chinol, Marco,Paganelli, Giovanni,Papi, Stefano,Chelli, Mario,Leone, Giuseppe,Papini, Anna Maria,De Luca, Angelo,Ginanneschi, Mauro
, p. 3170 - 3173 (2003)
The synthesis of a new biotin derivative, the (CO) reduced N-aminohexyl biotinamido derivative, designed to be serum biotinidase resistant, and its conjugation to the chelator DOTA through an amide bond at one of the four carboxymethyl chains are described. The 90Y-labeled conjugate was able to bind avidin at different Av/conjugate molar ratios with good results. The preclinical results indicate that this new biotin-DOTA conjugate is a good candidate for pretargeted diagnosis and therapy of tumors.
Photocleavable ligands for protein decoration of DNA nanostructures
Brglez, Josipa,Ahmed, Ishtiaq,Niemeyer, Christof M.
, p. 5102 - 5104 (2015)
This work describes the synthesis of amino-reactive, photocleavable hapten-modifiers and their application as affinity tags for DNA nanostructures. In particular, N-hydroxysuccinimide-activated linkers containing an α-methyl-nitroveratryl-butyric acid group and carboxyfluorescein or biotin were synthesized and coupled to alkyl-amino-modified DNA oligonucleotides. The resulting conjugates were then incorporated into DNA origami nanostructures. As demonstrated by electrophoresis and AFM imaging, the functionalized nanostructures were capable to bind cognate proteins which could then be cleaved-off by irradiation. Owing to its modularity, this approach to control protein binding should be useful for a wide variety of functional DNA nanostructures.
Biotin-decorated all-HPMA polymeric micelles for paclitaxel delivery
Wang, Yan,van Steenbergen, Mies J.,Beztsinna, Nataliia,Shi, Yang,Lammers, Twan,van Nostrum, Cornelus F.,Hennink, Wim E.
, p. 970 - 984 (2020)
To avoid poly(ethylene glycol)-related issues of nanomedicines such as accelerated blood clearance, fully N-2-hydroxypropyl methacrylamide (HPMAm)-based polymeric micelles decorated with biotin for drug delivery were designed. To this end, a biotin-functionalized chain transfer agent (CTA), 4-cyano-4-[(dodecylsulfanylthiocarbonyl)-sulfanyl]pentanoic acid (biotin-CDTPA), was synthesized for reversible addition–fragmentation chain-transfer (RAFT) polymerization. Amphiphilic poly(N-2-hydroxypropyl methacrylamide)-block-poly(N-2-benzoyloxypropyl methacrylamide) (p(HPMAm)-b-p(HPMAm-Bz)) with molecular weights ranging from 8 to 24 kDa were synthesized using CDTPA or biotin-CDTPA as CTA and 2,2′-azobis(2-methylpropionitrile) as initiator. The copolymers self-assembled in aqueous media into micelles with sizes of 40–90 nm which positively correlated to the chain length of the hydrophobic block in the polymers, whereas the critical micelle concentrations decreased with increasing hydrophobic block length. The polymer with a molecular weight of 22.1 kDa was used to prepare paclitaxel-loaded micelles which had sizes between 61 and 70 nm, and a maximum loading capacity of around 10 wt%. A549 lung cancer cells overexpressing the biotin receptor, internalized the biotin-decorated micelles more efficiently than non-targeted micelles, while very low internalization of both types of micelles by HEK293 human embryonic kidney cells lacking the biotin receptor was observed. As a consequence, the paclitaxel-loaded micelles with biotin decoration exhibited stronger cytotoxicity in A549 cells than non-targeted micelles. Overall, a synthetic pathway to obtain actively targeted poly(ethylene glycol)-free micelles fully based on a poly(HPMAm) backbone was established. These polymeric micelles are promising systems for the delivery of hydrophobic anticancer drugs.
PYRIDAZINONES AS PARP7 INHIBITORS
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Page/Page column 162-163; 165, (2021/05/07)
The present invention relates to pyridazinones and related compounds which are inhibitors of PARP7 and are useful in the treatment of cancer.
PYRIDAZINONES AS PARP7 INHIBITORS
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Page/Page column 65; 68, (2021/05/07)
The present invention relates to pyridazinones and related compounds which are inhibitors of PARP7 and are useful in the treatment of cancer.
In Vitro and Cellular Probes to Study PARP Enzyme Target Engagement
Blackwell, Danielle J.,Church, W. David,Desai, Hetvi J.,Keilhack, Heike,Kuntz, Kevin W.,Lu, Alvin Z.,Majer, Christina R.,Niepel, Mario,Perl, Nicholas R.,Ren, Yue,Santospago, Andrew G.,Schenkel, Laurie B.,Swinger, Kerren K.,Vasbinder, Melissa M.,Wigle, Tim J.
supporting information, p. 877 - 887 (2020/07/16)
Poly(ADP-ribose) polymerase (PARP) enzymes use nicotinamide adenine dinucleotide (NAD+) to modify up to seven different amino acids with a single mono(ADP-ribose) unit (MARylation deposited by PARP monoenzymes) or branched poly(ADP-ribose) polymers (PARylation deposited by PARP polyenzymes). To enable the development of tool compounds for PARP monoenzymes and polyenzymes, we have developed active site probes for use in in vitro and cellular biophysical assays to characterize active site-directed inhibitors that compete for NAD+ binding. These assays are agnostic of the protein substrate for each PARP, overcoming a general lack of knowledge around the substrates for these enzymes. The in vitro assays use less enzyme than previously described activity assays, enabling discrimination of inhibitor potencies in the single-digit nanomolar range, and the cell-based assays can differentiate compounds with sub-nanomolar potencies and measure inhibitor residence time in live cells. Wigle et al. describe a versatile set of NAD+-competitive probes for PARP enzymes that are used to build high-throughput in vitro and cellular biophysical assays that enable inhibitor screening and determination of residence time.
SOLID FORMS OF A PARP7 INHIBITOR
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Page/Page column 43; 45; 46, (2020/11/13)
The present invention relates to solid forms of the poly(ADP-ribose) polymerase 7 (PARP7) inhibitor 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one, and salts thereof, including methods of preparation thereof, where the inhibitor is useful in the treatment of cancer.
Strategy and validation of a structure-based method for the discovery of selective inhibitors of PAK isoforms and the evaluation of their anti-cancer activity
Song, Pei-Lu,Wang, Gang,Su, Yuan,Wang, Han-Xun,Wang, Jian,Li, Feng,Cheng, Mao-Sheng
, (2019/08/12)
p21 activated kinase 4 (PAK4), which belongs to the serine/threonine (Ser/Thr) protein kinase family, is a representative member of the PAK family and plays a significant role in multiple processes associated with cancer development. In this study, structure-based virtual screening was performed to discover novel and selective small molecule scaffolds, and a 6-hydroxy-2-mercapto-3-phenylpyrimidin-4(3H)-one-based compound (SPU-106, 14No.) was identified as an effective PAK4 inhibitor. By combining both a molecular docking study and molecular dynamics (MD) simulation strategies, the binding mode was determined in the PAK4 site. The SPU-106 compound could efficiently and selectively bind to the PAK4 kinase domain at an IC50 of 21.36 μM according to the kinase analysis. The designed molecular probe demonstrated that SPU-106 binds to the kinase domain in the C-terminus of PAK4. Further investigation revealed that the SPU-106 had a strong inhibitory effect on the invasion of SGC7901 cells but without any cytotoxicity. The western blot analysis indicated that the compound potently inhibited the PAK4/LIMK1/cofilin and PAK4/SCG10 signaling pathways. Thus, our work shows the successful application of computational strategies for the discovery of selective hits, and SPU-106 may be an effective PAK4 inhibitor for further development as an antitumor agent.
PYRIDAZINONES AS PARP7 INHIBITORS
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Paragraph 2101, (2019/11/11)
The present invention relates to pyridazinones and related compounds which are inhibitors of PARP7 and are useful in the treatment of cancer.
