- Compound capable of degrading Bcr-Abl or PARP as well as preparation method and pharmaceutical application thereof
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The invention relates to a compound shown in a general formula (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal of the compound, an intermediate and a preparation method of the compound, and application of the compound in Bcr-Abl or PARP related diseases such as tumors. The chemical formula is B-K(Ia)B-Cy1-K(Ib)B-Cy1-Cy2-K(Ic)B-Cy1-Cy2-Cy3-K(Id)B-Cy1-Cy2-Cy3-Cy4-K(Ie).
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- Construction of an IMiD-based azide library as a kit for PROTAC research
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As a promising protein degradation strategy, PROTAC technology is increasingly becoming a new star in cancer treatment. Here we report the efficient construction of an IMiD-based azide library via a quick one-step conversion of the existing IMiD-based ami
- Liu, Haixia,Sun, Renhong,Ren, Chaowei,Qiu, Xing,Yang, Xiaobao,Jiang, Biao
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supporting information
p. 166 - 170
(2021/01/18)
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- PROTEIN DEGRADATION TARGETING COMPOUND, ANTI-TUMOR APPLICATION, INTERMEDIATE THEREOF AND USE OF INTERMEDIATE
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The present disclosure relates to compounds of formula (I) and their anti-tumor uses, and their intermediates of formula (III), intermediates of formula (IV), and uses of the intermediates. The compound of formula (I) has a degrading effect on a specific target protein, which is mainly composed of three parts. The first part is a small molecule compound (SMBP, Small Molecules Binding Protein) that can bind to a protein, the second part LIN is a linker, and the three-part ULM is a ubiquitin ligand (ULM, Ubiquitin Ligase Binding Moiety), wherein SMBP is covalently bound to LIN, and LIN is covalently bound to ULM. A series of compounds designed and synthesized in the present disclosure have a wide range of pharmacological activities, including the functions of degrading specific proteins and/or inhibiting activities of specific proteins, and thus can be used in related tumor treatments.
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Paragraph 0382-0383
(2021/02/18)
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- Discovery of novel BCR-ABL PROTACs based on the cereblon E3 ligase design, synthesis, and biological evaluation
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Protein degradation is a promising strategy for drug development. Proteolysis-targeting chimeras (PROTACs) hijacking the E3 ligase cereblon (CRBN) exhibit enormous potential and universal degradation performance due to the small molecular weight of CRBN ligands. In this study, the CRBN-recruiting PROTACs were explored on the degradation of oncogenic fusion protein BCR-ABL, which drives the pathogenesis of chronic myeloid leukemia (CML). A series of novel PROTACs were synthesized by conjugating BCR-ABL inhibitor dasatinib to the CRBN ligand including pomalidomide and lenalidomide, and the extensive structure-activity relationship (SAR) studies were performed focusing on optimization of linker parameters. Therein, we uncovered that pomalidomide-based degrader 17 (SIAIS056), possessing sulfur-substituted carbon chain linker, exhibits the most potent degradative activity in vitro and favorable pharmacokinetics in vivo. Besides, degrader 17 also degrades a variety of clinically relevant resistance-conferring mutations of BCR-ABL. Furthermore, degrader 17 induces significant tumor regression against K562 xenograft tumors. Our study indicates that 17 as an efficacious BCR-ABL degrader warrants intensive investigation for the future treatment of BCR-ABL+ leukemia.
- Liu, Haixia,Ding, Xinyu,Liu, Linyi,Mi, Qianglong,Zhao, Quanju,Shao, YuBao,Ren, Chaowei,Chen, Jinju,Kong, Ying,Qiu, Xing,Elvassore, Nicola,Yang, Xiaobao,Yin, Qianqian,Jiang, Biao
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- BIFUNCTIONAL DEGRADERS AND THEIR METHODS OF USE
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Described herein are bifunctional degrader compounds, their various targets, their preparation, pharmaceutical compositions comprising them, and their use in the treatment of conditions, diseases, and disorders mediated by various target proteins.
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Page/Page column 334
(2021/04/01)
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- N-phenyl-2-(pyrimidin-4-ylamino)thiazol-5-carboxamide derivatives, pharmaceutically acceptable salts thereof and a whitening material composition containing the same as an active ingredient
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The present invention relates to a whitening material composition comprising an N-phenyl-2-(pyrimidin-4-ylamino)thiazole-5-carboxamide derivative as an active ingredient. Since the whitening material composition provided in one aspect of the present invention has an excellent effect of inhibiting the promotion of cell melanogenesis even when a small amount thereof is used, a cosmetic product for skin whitening and a product for preventing, alleviating, and treating melanin hyperpigmentation diseases can be usefully used.
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Paragraph 0096-0097; 0102-0105; 0112-0113; 0118-0121
(2020/11/03)
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- Anti-tumor drug dasatinib-RGD conjugate, preparation method and application thereof
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The invention is applicable to the technical field of medicine and provides an anti-tumor drug dasatinib-RGD conjugate, a preparation method and application thereof. The dasatinib-RGD conjugate provided by the invention is formed by connecting dasatinib and RGD through an amide bond. The preparation cost is low, the stability is good, the safety is good, and the conjugate meets the requirements ofclinical medication. The invention also provides nanomicelles composed of the anti-tumor drug dasatinib-RGD conjugate and a triblock polymer and anti-tumor application thereof. The dasatinib-RGD conjugate has high micellar drug loading, good stability and good biocompatibility, and in vivo tests show that the dasatinib-RGD conjugate can be efficiently accumulated in tumor tissues through active targeting and/or passive targeting, increases drug concentration in tumor tissues, has a good anti-tumor effect, realizes the effect-enhancing and toxicity-reducing purposes, and has a good market prospect and value.
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Paragraph 0045-0047
(2020/05/05)
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- COMPOUNDS TARGETING AND DEGRADING BCR-ABL PROTEIN AND ITS ANTITUMOR APPLICATION
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The present disclosure provides a compound of formula (I) targeting and degrading BCR-ABL protein and its use in the field of antitumor. The compound of formula (I) shows degradation and inhibitory effects on BCR-ABL target protein, which is mainly comprised of four moieties, wherein the first moiety (BCR-ABL-TKIs) is compound moiety with BCR-ABL tyrosine kinase inhibited activity; the second moiety (the LIN) is link units; the third moiety (the ULM) is a small molecule ligand for VHL or CRBN proteases with ubiquitination; and the four moiety (the group A) is carbonyl group that covalently binds to BCR-ABL-TKIs and LIN, and the LIN is further covalently bonded to ULM. A series of compounds designed and synthesized by the present disclosure shows extensive pharmacological effective, which function to degrade BCR-ABL protein and inhibit BCR-ABL effective, and can be utilized for treating relevant tumor.
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Paragraph 0155-0156
(2021/01/26)
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- Azo-protac: Novel light-controlled small-molecule tool for protein knockdown
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Reversibly altering endogenous protein levels are persistent issues. Herein, we designed photoswitchable azobenzene-proteolysis targeting chimeras (Azo-PROTACs) by including azobenzene moieties between ligands for the E3 ligase and the protein of interest
- Jin, Yu-Hui,Lu, Meng-Chen,Wang, Yan,Shan, Wen-Xin,Wang, Xuan-Yu,You, Qi-Dong,Jiang, Zheng-Yu
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p. 4644 - 4654
(2020/06/08)
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- Global PROTAC Toolbox for Degrading BCR-ABL Overcomes Drug-Resistant Mutants and Adverse Effects
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The BCR-ABL fusion oncoprotein causes chronic myeloid leukemia or acute lymphoblastic leukemia in Ph+ patients because the ABL kinase is constitutively activated. However, current clinical treatment with ABL inhibitors is seriously limited by drug resistance and adverse effects. Although the emerging proteolysis-Targeting chimeras (PROTACs) have been introduced to degrade BCR-ABL, most of them showed limited activity and could not overcome the common drug-resistant mutants, especially for T315I mutant. Herein, we systematically designed a set of unique PROTACs by globally targeting all the three binding sites of BCR-ABL, including dasatinib-, ponatinib-, and asciminib-based PROTACs. Our ponatinib-based PROTACs showed practical activity as dasatinib-based PROTACs, while no reported ponatinib-based PROTACs could degrade BCR-ABL before. As a proof of concept, some additional dasatinib-based PROTACs were then designed to degrade T315I mutant too. We provided a global PROTAC toolbox for degrading both wild-Type and T315I-mutated BCR-ABL from each binding site. More importantly, these PROTACs showed better selectivity and less adverse effects than the inhibitors, indicating that PROTACs had great potential for overcoming clinical drug resistance and safety issues.
- Yang, Yiqing,Gao, Hongying,Sun, Xiuyun,Sun, Yonghui,Qiu, Yueping,Weng, Qinjie,Rao, Yu
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p. 8567 - 8583
(2020/09/16)
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- Controlling cellular distribution of drugs with permeability modifying moieties
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Phenotypic screening provides compounds with very limited target cellular localization data. In order to select the most appropriate target identification methods, determining if a compound acts at the cell-surface or intracellularly can be very valuable. In addition, controlling cell-permeability of targeted therapeutics such as antibody-drug conjugates (ADCs) and targeted nanoparticle formulations can reduce toxicity from extracellular release of drug in undesired tissues or direct activity in bystander cells. By incorporating highly polar, anionic moieties via short polyethylene glycol linkers into compounds with known intracellular, and cell-surface targets, we have been able to correlate the cellular activity of compounds with their subcellular site of action. For compounds with nuclear (Brd, PARP) or cytosolic (dasatinib, NAMPT) targets, addition of the permeability modifying group (small sulfonic acid, polycarboxylic acid, or a polysulfonated fluorescent dye) results in near complete loss of biological activity in cell-based assays. For cell-surface targets (H3, 5HT1A, β2AR) significant activity was maintained for all conjugates, but the results were more nuanced in that the modifiers impacted binding/activity of the resulting conjugates. Taken together, these results demonstrate that small anionic compounds can be used to control cell-permeability independent of on-target activity and should find utility in guiding target deconvolution studies and controlling drug distribution of targeted therapeutics.
- Richardson, Paul L.,Marin, Violeta L.,Koeniger, Stormy L.,Baranczak, Aleksandra,Wilsbacher, Julie L.,Kovar, Peter J.,Bacon-Trusk, Patricia E.,Cheng, Min,Hopkins, Todd A.,Haman, Sandra T.,Vasudevan, Anil
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supporting information
p. 974 - 984
(2019/06/27)
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- Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting von Hippel-Lindau (VHL) E3 Ubiquitin Ligase
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The oncogenic fusion protein BCR-ABL is the driving force of leukemogenesis in chronic myeloid leukemia (CML). Despite great progress for CML treatment through application of tyrosine kinase inhibitors (TKIs) against BCR-ABL, long-term drug administration and clinical resistance continue to be an issue. Herein, we described the design, synthesis, and evaluation of novel proteolysis-targeting chimeric (PROTAC) small molecules targeting BCR-ABL which connect dasatinib and VHL E3 ubiquitin ligase ligand by extensive optimization of linkers. Our efforts have yielded SIAIS178 (19), which induces proper interaction between BCR-ABL and VHL ligase leading to effective degradation of BCR-ABL protein, achieves significant growth inhibition of BCR-ABL+ leukemic cells in vitro, and induces substantial tumor regression against K562 xenograft tumors in vivo. In addition, SIAIS178 also degrades several clinically relevant resistance-conferring mutations. Our data indicate that SIAIS178 as efficacious BCR-ABL degrader warrants extensive further investigation for the treatment of BCR-ABL+ leukemia.
- Zhao, Quanju,Ren, Chaowei,Liu, Linyi,Chen, Jinju,Shao, Yubao,Sun, Ning,Sun, Renhong,Kong, Ying,Ding, Xinyu,Zhang, Xianfang,Xu, Youwei,Yang, Bei,Yin, Qianqian,Yang, Xiaobao,Jiang, Biao
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p. 9281 - 9298
(2019/10/16)
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- Protein targeting degradation chimeric molecule and preparation method and application of protein targeting degradation chimeric molecule
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The invention discloses a protein targeting degradation chimeric molecule and a preparation method and application of the protein targeting degradation chimeric molecule. The protein targeting degradation chimeric molecule can restrain the expression of a
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Paragraph 0028; 0030; 0086-0089
(2019/06/07)
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- A convenient new and efficient commercial synthetic route for dasatinib (Sprycel)
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A new and efficient synthetic route for dual-Src/Abl kinase inhibitor dasatinib (Sprycel), an anticancer drug, is described. This commercially viable process yields dasatinib monohydrate free of potential impurities with consistent yield of 68% in route A and 61% in route B with HPLC purity >99.80% over four stages.
- Suresh, Garbapu,Nadh, Ratnakaram Venkata,Srinivasu, Navuluri,Yennity, Durgaprasad
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supporting information
p. 1610 - 1621
(2017/09/08)
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- Synthesis and biological evaluation of novel dasatinib analogues as potent DDR1 and DDR2 kinase inhibitors
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Novel dasatinib analogues as DDR1 and DDR2 inhibitors were designed and synthesized. The synthesized compounds were screened for DDR1 and DDR2 kinase inhibitory and cancer cell proliferation inhibitory activities. Some of the compounds showed the potent i
- Liu, Lu,Hussain, Muzammal,Luo, Jinfeng,Duan, Anna,Chen, Chaonan,Tu, Zhengchao,Zhang, Jiancun
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p. 420 - 427
(2017/04/03)
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- Tyrosine kinase inhibitor and preparation method and use thereof
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The invention relates to a tyrosine kinase inhibitor and a preparation method and use thereof, and belongs to the technical field of pharmaceutical chemistry. The tyrosine kinase inhibitor having the structural features shown in the general formula I, or its pharmaceutically acceptable salts or stereoisomers can effectively inhibit tyrosine kinase activity, and can inhibit kinases such as DDR1, DDR2, Abl, Src, Btk and Kit. Compared with a positive contrast dasatinib, the tyrosine kinase inhibitor has higher half inhibitory concentration or the same half inhibitory concentration, and especially, aiming at DDR1, DDR2, Src, Btk and Kit, the compound 8j has lower K562 cell half inhibitory concentration. The tyrosine kinase inhibitor has good enzyme inhibitory activity and cell activity and has a large application prospect.
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- Design and synthesis of novel dasatinib analogues
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Design, synthesis, characterization and in vitro biological assay of a series of novel carboxylic acid and amino acid analogs of dasatinib (1) as anticancer agents are reported. Some of the synthesized analogs were identified as potent Src/Abl kinase inhibitors with greater antiproliferative activity against K652 and T315I cancer cell lines. The synthetic process involves condensation of N-(2-chloro-6-methylphenyl)-2-[[6-[4(-1-pipearazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide with carboxylic acids in the presence of dicyclohexylcarbodiimide and oxyma in organic solvent medium. Compounds were characterized and tested for anticancer activity on leukemia cancer cell lines K562 and Baf3/T315. Analogues of lactic acid, mandalic acid, leucine and proline have shown promising antiproliferative activity compared to dasatinib.
- Buchappa,Durgaprasad,Suneelkumar,Rani, P. Baby,Babu, K. Ravi,Rao, A. K. S. Bhujanga,Aparna
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p. 1275 - 1280
(2016/04/10)
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- TYROSINE KINASE INHIBITORS CONTAINING A ZINC BINDING MOIETY
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The present invention relates to tyrosine kinase inhibitors that contain a zinc-binding moiety and their use in the treatment of tyrosine related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.
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Page/Page column 58
(2008/06/13)
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- Synthesis and biological evaluation of a fluorine-18 derivative of dasatinib
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Tyrosine kinases often play pivotal roles in the pathogenesis of cancer and are good candidates for therapeutic intervention and targeted molecular imaging. The precursor synthesis, radiosynthesis, and biological characterization of a fluorine-18 analog o
- Veach, Darren R.,Namavari, Mohammad,Pillarsetty, Nagavarakishore,Santos, Elmer B.,Beresten-Kochetkov, Tatiana,Lambek, Caryl,Punzalan, Blesida J.,Antczak, Christophe,Smith-Jones, Peter M.,Djaballah, Hakim,Clarkson, Bayard,Larson, Steven M.
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p. 5853 - 5857
(2008/04/05)
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- 'N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamides metabolites
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The present invention is directed to metabolites of ′N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, the compound of formula (I), pharmaceutical compositions thereof, and to methods
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Page/Page column 28
(2008/06/13)
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