859027-32-0Relevant articles and documents
PROTEIN DEGRADATION TARGETING COMPOUND, ANTI-TUMOR APPLICATION, INTERMEDIATE THEREOF AND USE OF INTERMEDIATE
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Paragraph 0386; 0388, (2021/02/18)
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.
DEGRADATION OF PROTEIN KINASES BY CONJUGATION OF PROTEIN KINASE INHIBITORS WITH E3 LIGASE LIGAND AND METHODS OF USE
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Page/Page column 118, (2018/05/27)
The present application provides bifunctional compounds of Formula (I), or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for protein kinases (e.g., Bcr-Abl). The present application also relates to methods for the targeted degradation of one or more protein kinases through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to one or more protein kinases which can be utilized in the treatment of disorders modulated by protein kinases.
BCR-ABL DIPLOID INHIBITOR, PREPARATION METHOD THEREFOR, AND USES THEREOF
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Paragraph 0042-0044, (2017/03/08)
Disclosed are compounds or pharmaceutically acceptable salts thereof having the following general formula: R-Linker-R. The compounds or pharmaceutically acceptable salts thereof provided by the present invention are used as Bcr-Abl diploid inhibitors, whi
SUBSTITUTED PYRIMIDINYL AND PYRIDINYL-PYRROLOPYRIDINONES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS
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Page/Page column 40; 42, (2014/05/24)
The present invention relates to substituted pyrimidinyl- and pyridinylpyrrolopyridinone compounds which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular RET family kinases. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions containing these compounds.
Discovery of 3-[2-(imidazo[1,2- b ]pyridazin-3-yl)ethynyl]-4-methyl- N -{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant
Huang, Wei-Sheng,Metcalf, Chester A.,Sundaramoorthi, Raji,Wang, Yihan,Zou, Dong,Thomas, R. Mathew,Zhu, Xiaotian,Cai, Lisi,Wen, David,Liu, Shuangying,Romero, Jan,Qi, Jiwei,Chen, Ingrid,Banda, Geetha,Lentini, Scott P.,Das, Sasmita,Xu, Qihong,Keats, Jeff,Wang, Frank,Wardwell, Scott,Ning, Yaoyu,Snodgrass, Joseph T.,Broudy, Marc I.,Russian, Karin,Zhou, Tianjun,Commodore, Lois,Narasimhan, Narayana I.,Mohemmad, Qurish K.,Iuliucci, John,Rivera, Victor M.,Dalgarno, David C.,Sawyer, Tomi K.,Clackson, Tim,Shakespeare, William C.
experimental part, p. 4701 - 4719 (2010/10/03)
In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of Ile315 side chain. Extensive SAR studies led to the discovery of development candidate 20g (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC 50s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABLT315I expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of 20g to be an effective treatment for CML, including patients refractory to all currently approved therapies.
