Category: 882562-40-5

Name: 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole. Aromatic heterocyclic compounds can also be classified according to the number of heteroatoms contained in the heterocycle: single heteroatom, two heteroatoms, three heteroatoms and four heteroatoms. Compound: 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole, is researched, Molecular C18H11Cl2N3O2S, CAS is 882562-40-5, about Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Author is 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..

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

Epoxy compounds usually have stronger nucleophilic ability, because the alkyl group on the oxygen atom makes the bond angle smaller, which makes the lone pair of electrons react more dissimilarly with the electron-deficient system. 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.Recommanded Product: 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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Reference:
Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Application of 882562-40-5. The reaction of aromatic heterocyclic molecules with protons is called protonation. Aromatic heterocycles are more basic than benzene due to the participation of heteroatoms. 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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Reference:
Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Application of 882562-40-5. The reaction of aromatic heterocyclic molecules with protons is called protonation. Aromatic heterocycles are more basic than benzene due to the participation of heteroatoms. 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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Reference:
Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Most of the natural products isolated at present are heterocyclic compounds, so heterocyclic compounds occupy an important position in the research of organic chemistry. A compound: 882562-40-5, is researched, SMILESS is ClC1=NC(C2=CN(C3=C2C=CC=C3)S(=O)(=O)C2=CC=CC=C2)=C(Cl)C=N1, Molecular C18H11Cl2N3O2SJournal, Article, Research Support, Non-U.S. Gov’t, Journal of the American Chemical Society called Targeting the Gatekeeper MET146 of C-Jun N-Terminal Kinase 3 Induces a Bivalent Halogen/Chalcogen Bond, Author is 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., the main research direction is aminopyrimidine inhibitor halogen chalcogen bond methionine JNK3 crystal structure.Category: tetrahydroisoquinoline.

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%).

This literature about this compound(882562-40-5)Category: tetrahydroisoquinolinehas given us a lot of inspiration, and I hope that the research on this compound(3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole) can be further advanced. Maybe we can get more compounds in a similar way.

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

In organic chemistry, atoms other than carbon and hydrogen are generally referred to as heteroatoms. The most common heteroatoms are nitrogen, oxygen and sulfur. Now I present to you an article called Targeting the Gatekeeper MET146 of C-Jun N-Terminal Kinase 3 Induces a Bivalent Halogen/Chalcogen Bond, published in 2015-11-25, which mentions a compound: 882562-40-5, mainly applied to aminopyrimidine inhibitor halogen chalcogen bond methionine JNK3 crystal structure, HPLC of Formula: 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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Reference:
Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Product Details of 882562-40-5. 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 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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Reference:
Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

The three-dimensional configuration of the ester heterocycle is basically the same as that of the carbocycle. Compound: 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole(SMILESS: ClC1=NC(C2=CN(C3=C2C=CC=C3)S(=O)(=O)C2=CC=CC=C2)=C(Cl)C=N1,cas:882562-40-5) is researched.HPLC of Formula: 693-67-4. The article 《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》 in relation to this compound, is published in European Journal of Medicinal Chemistry. Let’s take a look at the latest research on this compound (cas: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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Reference:
Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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.Application of 882562-40-5.Ward, Richard A.; Anderton, Mark J.; Ashton, Susan; Bethel, Paul A.; Box, Matthew; Butterworth, Sam; Colclough, Nicola; Chorley, Christopher G.; Chuaqui, Claudio; Cross, Darren A. E.; Dakin, Les A.; Debreczeni, Judit E.; Eberlein, Cath; Finlay, M. Raymond V.; Hill, George B.; Grist, Matthew; Klinowska, Teresa C. M.; Lane, Clare; Martin, Scott; Orme, Jonathon P.; Smith, Peter; Wang, Fengjiang; Waring, Michael J. published the article 《Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR)》 about this compound( cas:882562-40-5 ) in Journal of Medicinal Chemistry. Keywords: EGFR activating gatekeeper mutant covalent inhibitor SAR. Let’s learn more about this compound (cas:882562-40-5).

A novel series of small-mol. inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by mol. modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clin. efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quant. structure-property relationship (QSPR) to support design.

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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, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov’t, Nature Chemical Biology called 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., 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, Name: 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole.

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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Reference:
Tetrahydroisoquinoline – Wikipedia,
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