- 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 0371-0372; 0379
(2021/02/18)
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- Development of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance
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EML4-ALK and NPM-ALK fusion proteins possess constitutively activated ALK (anaplastic lymphoma kinase) activity, which in turn leads to the development of non-small cell lung cancer and anaplastic large-cell lymphomas (ALCLs). FDA-approved ALK inhibitor drugs cause significant cancer regression. However, drug resistance eventually occurs and it becomes a big obstacle in clinic. Novel proteolysis targeting chimera (PROTAC) technology platform provides a potential therapeutic strategy for drug resistance. Herein, we designed and synthesized a series of ALK PROTACs based on Brigatinib and VHL-1 conjunction, and screened SIAIS117 as the best degrader which not only blocked the growth of SR and H2228 cancer cell lines, but also degraded ALK protein. In addition, SIAIS117 also showed much better growth inhibition effect than Brigatinib on 293T cell line that exogenously expressed G1202R-resistant ALK proteins. Furthermore, it also degraded G1202R mutant ALK protein in vitro. At last, it has the potentially anti-proliferation ability of small cell lung cancer. Thus, we have successfully generated the degrader SIAIS117 that can potentially overcome resistance in cancer targeted therapy.
- Chen, Jinju,Jiang, Biao,Kong, Ying,Li, Yan,Lin, Haifan,Qiu, Xing,Ren, Chaowei,Song, Xiaoling,Sun, Ning,Yang, Xiaobao,Zhang, Jianshui,Zhong, Hui,Zhou, Yuedong
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- ALK (anaplastic lymphoma kinase) protein degradation agent and anti-tumor application thereof
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The invention discloses a compound in a formula (I) and an anti-tumor application thereof. The compound in the formula (I) has degradation and inhabitation functions on ALK target protein and mainly comprises four parts, the first part ALK-TKIs is a compound with ALK tyrosine kinase inhabitation activity; the second part LIN is different linkers; the third part ULM (ubiquitin ligase binding moiety) of VHL, CRBN or other protease micromolecular ligand with a ubiquitination function; the fourth part group A is carboxyl or deficiency and covalently binds ALK-TKIs with LIN and covalently binds LINwith ULM. A series of designed and synthesized compounds have wide pharmacological activity, have functions of degrading ALK protein and inhibiting ALK activity and can be applied to related tumor therapy.
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Paragraph 0358; 0359-0360; 0374-0377
(2019/07/04)
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- Preparation method and crystal form of deuterated diphenyl amino pyrimidine compound
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The present invention discloses a preparation method and a crystal form of a compound shown in the formula (A) and also discloses a pharmaceutical composition comprising the crystal form of the compound shown in the formula (A) and a method for treating A
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Paragraph 0362-0366
(2019/04/27)
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- Diaminopyrimidine compound and composition containing same
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The invention provides a diaminopyrimidine compound and a composition containing the same and discloses the diaminopyrimidine compound shown as in a formula (I) and a drug combination containing the compound or salt thereof acceptable in crystal form and
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Paragraph 0112; 0113; 0119; 0120
(2017/06/02)
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- CHEMICAL COMPOUNDS
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The present invention relates to compounds of Formula (I) and/or Formula (Ia): and to their salts, pharmaceutical compositions, methods of use, and methods for their preparation. These compounds inhibit ALK kinase activity, and thus may be used for the tr
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Page/Page column 25
(2012/02/06)
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- 2- [ (2-{PHENYLAMINO}-1H-PYRROLO [2, 3-D] PYRIMIDIN-4-YL) AMINO] BENZAMIDE DERIVATIVES AS IGF-1R INHIBITORS FOR THE TREATMENT OF CANCER
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Novel pyrrolopyrimidines as shown in formula (I) and pharmaceutically acceptable derivatives thereof. The compounds are useful in the inhibition of IGF-1R.
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Page/Page column 146-147
(2009/04/25)
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