Category: 882562-40-5

Quality Control of 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole. The protonation of heteroatoms in aromatic heterocycles can be divided into two categories: lone pairs of electrons are in the aromatic ring conjugated system; and lone pairs of electrons do not participate. Compound: 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole, is researched, Molecular C18H11Cl2N3O2S, CAS is 882562-40-5, about Discovery and resistance mechanism of a selective CDK12 degrader. Author is Jiang, Baishan; Gao, Yang; Che, Jianwei; Lu, Wenchao; Kaltheuner, Ines H.; Dries, Ruben; Kalocsay, Marian; Berberich, Matthew J.; Jiang, Jie; You, Inchul; Kwiatkowski, Nicholas; Riching, Kristin M.; Daniels, Danette L.; Sorger, Peter K.; Geyer, Matthias; Zhang, Tinghu; Gray, Nathanael S..

Cyclin-dependent kinase 12 (CDK12) is an emerging therapeutic target due to its role in regulating transcription of DNA-damage response (DDR) genes. However, development of selective small mols. targeting CDK12 has been challenging due to the high degree of homol. between kinase domains of CDK12 and other transcriptional CDKs, most notably CDK13. In the present study, the rational design and characterization of a CDK12-specific degrader, BSJ-4-116 (I), is reported. BSJ-4-116 selectively degraded CDK12 as assessed through quant. proteomics. Selective degradation of CDK12 resulted in premature cleavage and poly(adenylation) of DDR genes. Moreover, BSJ-4-116 exhibited potent antiproliferative effects, alone and in combination with the poly(ADP-ribose) polymerase inhibitor olaparib, as well as when used as a single agent against cell lines resistant to covalent CDK12 inhibitors. Two point mutations in CDK12 were identified that confer resistance to BSJ-4-116, demonstrating a potential mechanism that tumor cells can use to evade bivalent degrader mols.

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Tetrahydroisoquinoline – Wikipedia,
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Name: 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole. The fused heterocycle is formed by combining a benzene ring with a single heterocycle, or two or more single heterocycles. Compound: 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole, is researched, Molecular C18H11Cl2N3O2S, CAS is 882562-40-5, about Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Author is Kwiatkowski, Nicholas; Zhang, Tinghu; Rahl, Peter B.; Abraham, Brian J.; Reddy, Jessica; Ficarro, Scott B.; Dastur, Anahita; Amzallag, Arnaud; Ramaswamy, Sridhar; Tesar, Bethany; Jenkins, Catherine E.; Hannett, Nancy M.; McMillin, Douglas; Sanda, Takaomi; Sim, Taebo; Kim, Nam Doo; Look, Thomas; Mitsiades, Constantine S.; Weng, Andrew P.; Brown, Jennifer R.; Benes, Cyril H.; Marto, Jarrod A.; Young, Richard A.; Gray, Nathanael S..

Tumor oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacol. inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here the authors present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide anal. in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumor cells. Pharmacol. modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumor types that are dependent on transcription for maintenance of the oncogenic state.

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Most of the compounds have physiologically active properties, and their biological properties are often attributed to the heteroatoms contained in their molecules, and most of these heteroatoms also appear in cyclic structures. A Journal, Article, Journal of Medicinal Chemistry called Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7, Author is Marineau, Jason J.; Hamman, Kristin B.; Hu, Shanhu; Alnemy, Sydney; Mihalich, Janessa; Kabro, Anzhelika; Whitmore, Kenneth Matthew; Winter, Dana K.; Roy, Stephanie; Ciblat, Stephane; Ke, Nan; Savinainen, Anneli; Wilsily, Ashraf; Malojcic, Goran; Zahler, Robert; Schmidt, Darby; Bradley, Michael J.; Waters, Nigel J.; Chuaqui, Claudio, which mentions a compound: 882562-40-5, SMILESS is ClC1=NC(C2=CN(C3=C2C=CC=C3)S(=O)(=O)C2=CC=CC=C2)=C(Cl)C=N1, Molecular C18H11Cl2N3O2S, Related Products of 882562-40-5.

CDK7 has emerged as an exciting target in oncol. due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.

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Diab, Sarah; Yu, Mingfeng; Wang, Shudong published an article about the compound: 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole( cas:882562-40-5,SMILESS:ClC1=NC(C2=CN(C3=C2C=CC=C3)S(=O)(=O)C2=CC=CC=C2)=C(Cl)C=N1 ).Reference of 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole. Aromatic heterocyclic compounds can be classified according to the number of heteroatoms or the size of the ring. The authors also want to convey more information about this compound (cas:882562-40-5) through the article.

A review. Cyclin-dependent kinase (CDK) 7 has a unique functional repertoire by virtue of its dual role in transcription and cell cycle progression. Whereas CDK7 is ubiquitously expressed in various types of cancer, its downregulation leads to reduced cell proliferation. Importantly, it is now agreed that targeting transcription selectively limits the synthesis of mRNAs involved in tumor growth without causing an outage of transcription of housekeeping genes. Thus, CDK7 has been considered as a viable therapeutic target in cancer. Indeed, the development of CDK7 inhibitors has gained huge momentum with two mols., CT7001 and SY-1365, currently under clin. development. Herein, we discuss the latest understanding of the role of CDK7 in cancer cells and provide an overview of the pharmacophores of CDK7 inhibitors, their efficacy in various cancer models, and their clin. development.

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The preparation of ester heterocycles mostly uses heteroatoms as nucleophilic sites, which are achieved by intramolecular substitution or addition reactions. Compound: 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole( cas:882562-40-5 ) is researched.HPLC of Formula: 882562-40-5.Kwiatkowski, Nicholas; Zhang, Tinghu; Rahl, Peter B.; Abraham, Brian J.; Reddy, Jessica; Ficarro, Scott B.; Dastur, Anahita; Amzallag, Arnaud; Ramaswamy, Sridhar; Tesar, Bethany; Jenkins, Catherine E.; Hannett, Nancy M.; McMillin, Douglas; Sanda, Takaomi; Sim, Taebo; Kim, Nam Doo; Look, Thomas; Mitsiades, Constantine S.; Weng, Andrew P.; Brown, Jennifer R.; Benes, Cyril H.; Marto, Jarrod A.; Young, Richard A.; Gray, Nathanael S. published the article 《Targeting transcription regulation in cancer with a covalent CDK7 inhibitor》 about this compound( cas:882562-40-5 ) in Nature (London, United Kingdom). Keywords: THZ1 THZ1R bioTHZ1 preparation transcription regulation antitumor CDK7 inhibitor; phenylaminopyrimidine derivative THZ1 preparation antitumor CDK7 inhibitor transcription. Let’s learn more about this compound (cas:882562-40-5).

Tumor oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacol. inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here the authors present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide anal. in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumor cells. Pharmacol. modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumor types that are dependent on transcription for maintenance of the oncogenic state.

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Tetrahydroisoquinoline – Wikipedia,
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Most of the compounds have physiologically active properties, and their biological properties are often attributed to the heteroatoms contained in their molecules, and most of these heteroatoms also appear in cyclic structures. A Journal, Article, European Journal of Medicinal Chemistry called Structure-activity relationship study of THZ531 derivatives enables the discovery of BSJ-01-175 as a dual CDK12/13 covalent inhibitor with efficacy in Ewing sarcoma, Author is Jiang, Baishan; Jiang, Jie; Kaltheuner, Ines H.; Iniguez, Amanda Balboni; Anand, Kanchan; Ferguson, Fleur M.; Ficarro, Scott B.; Seong, Bo Kyung Alex; Greifenberg, Ann Katrin; Dust, Sofia; Kwiatkowski, Nicholas P.; Marto, Jarrod A.; Stegmaier, Kimberly; Zhang, Tinghu; Geyer, Matthias; Gray, Nathanael S., which mentions a compound: 882562-40-5, SMILESS is ClC1=NC(C2=CN(C3=C2C=CC=C3)S(=O)(=O)C2=CC=CC=C2)=C(Cl)C=N1, Molecular C18H11Cl2N3O2S, Related Products of 882562-40-5.

Development of inhibitors targeting CDK12/13 is of increasing interest as a potential therapy for cancers as these compounds inhibit transcription of DNA damage response (DDR) genes. We previously described THZ531, a covalent inhibitor with selectivity for CDK12/13. In order to elucidate structure-activity relationship (SAR), we have undertaken a medicinal chem. campaign and established a focused library of THZ531 analogs. Among these analogs, BSJ-01-175 demonstrates exquisite selectivity, potent inhibition of RNA polymerase II phosphorylation, and downregulation of CDK12-targeted genes in cancer cells. A 3.0 Å co-crystal structure with CDK12/CycK provides a structural rational for selective targeting of Cys1039 located in a C-terminal extension from the kinase domain. With moderate pharmacokinetic properties, BSJ-01-175 exhibits efficacy against an Ewing sarcoma tumor growth in a patient-derived xenograft (PDX) mouse model following 10 mg/kg once a day, i.p. administration. Taken together, BSJ-01-175 represents the first selective CDK12/13 covalent inhibitor with in vivo efficacy reported to date.

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Tetrahydroisoquinoline – Wikipedia,
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Alam, Mahbub; Beevers, Rebekah E.; Ceska, Tom; Davenport, Richard J.; Dickson, Karen M.; Fortunato, Mara; Gowers, Lewis; Haughan, Alan F.; James, Lynwen A.; Jones, Mark W.; Kinsella, Natasha; Lowe, Christopher; Meissner, Johannes W. G.; Nicolas, Anne-Lise; Perry, Benjamin G.; Phillips, David J.; Pitt, William R.; Platt, Adam; Ratcliffe, Andrew J.; Sharpe, Andrew; Tait, Laura J. published an article about the compound: 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole( cas:882562-40-5,SMILESS:ClC1=NC(C2=CN(C3=C2C=CC=C3)S(=O)(=O)C2=CC=CC=C2)=C(Cl)C=N1 ).Formula: C18H11Cl2N3O2S. Aromatic heterocyclic compounds can be classified according to the number of heteroatoms or the size of the ring. The authors also want to convey more information about this compound (cas:882562-40-5) through the article.

The development of a series of aminopyrimidines, e.g., I, as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, JNK2 and CDK2, and the in vitro inhibitory value for a c-Jun cellular assay were discussed.

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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Category: tetrahydroisoquinoline. So far, in addition to halogen atoms, other non-metallic atoms can become part of the aromatic heterocycle, and the target ring system is still aromatic. Compound: 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole, is researched, Molecular C18H11Cl2N3O2S, CAS is 882562-40-5, about Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7.

CDK7 has emerged as an exciting target in oncol. due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.

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Tetrahydroisoquinoline – Wikipedia,
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Zhang, Tinghu; Kwiatkowski, Nicholas; Olson, Calla M.; Dixon-Clarke, Sarah E.; Abraham, Brian J.; Greifenberg, Ann K.; Ficarro, Scott B.; Elkins, Jonathan M.; Liang, Yanke; Hannett, Nancy M.; Manz, Theresa; Hao, Mingfeng; Bartkowiak, Bartlomiej; Greenleaf, Arno L.; Marto, Jarrod A.; Geyer, Matthias; Bullock, Alex N.; Young, Richard A.; Gray, Nathanael S. published an article about the compound: 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole( cas:882562-40-5,SMILESS:ClC1=NC(C2=CN(C3=C2C=CC=C3)S(=O)(=O)C2=CC=CC=C2)=C(Cl)C=N1 ).SDS of cas: 882562-40-5. Aromatic heterocyclic compounds can be classified according to the number of heteroatoms or the size of the ring. The authors also want to convey more information about this compound (cas:882562-40-5) through the article.

Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12-cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small mols. capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.

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So far, in addition to halogen atoms, other non-metallic atoms can become part of the aromatic heterocycle, and the target ring system is still aromatic.Lange, Andreas; Guenther, Marcel; Buettner, Felix Michael; Zimmermann, Markus O.; Heidrich, Johannes; Hennig, Susanne; Zahn, Stefan; Schall, Christoph; Sievers-Engler, Adrian; Ansideri, Francesco; Koch, Pierre; Laemmerhofer, Michael; Stehle, Thilo; Laufer, Stefan A.; Boeckler, Frank M. researched the compound: 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole( cas:882562-40-5 ).SDS of cas: 882562-40-5.They published the article 《Targeting the Gatekeeper MET146 of C-Jun N-Terminal Kinase 3 Induces a Bivalent Halogen/Chalcogen Bond》 about this compound( cas:882562-40-5 ) in Journal of the American Chemical Society. Keywords: aminopyrimidine inhibitor halogen chalcogen bond methionine JNK3 crystal structure. We’ll tell you more about this compound (cas:882562-40-5).

We target the gatekeeper MET146 of c-Jun N-terminal kinase 3 (JNK3) to exemplify the applicability of X···S halogen bonds in mol. design using computational, synthetic, structural and biophys. techniques. In a designed series of aminopyrimidine-based inhibitors, we unexpectedly encounter a plateau of affinity. Compared to their QM-calculated interaction energies, particularly bromine and iodine fail to reach the full potential according to the size of their σ-hole. Instead, mutation of the gatekeeper residue into leucine, alanine, or threonine reveals that the heavier halides can significantly influence selectivity in the human kinome. Thus, we demonstrate that, although the choice of halogen may not always increase affinity, it can still be relevant for inducing selectivity. Determining the crystal structure of the iodine derivative in complex with JNK3 (4X21) reveals an unusual bivalent halogen/chalcogen bond donated by the ligand and the back-pocket residue MET115. Incipient repulsion from the too short halogen bond increases the flexibility of Cε of MET146, whereas the rest of the residue fails to adapt being fixed by the chalcogen bond. This effect can be useful to induce selectivity, as the necessary combination of methionine residues only occurs in 9.3% of human kinases, while methionine is the predominant gatekeeper (39%).

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