1001020-08-1Relevant articles and documents
Design, synthesis and biological evaluation of novel tetrahydrothieno [2,3-c]pyridine substitued benzoyl thiourea derivatives as PAK1 inhibitors in triple negative breast cancer
Yao, Dahong,Huang, Jian,Wang, Jinhui,He, Zhendan,Zhang, Jin
, p. 1524 - 1538 (2020)
The overexpression of P21-activated kinase 1 (PAK1) is associated with poor prognosis in several cancers, which has emerged as a promising drug targets. Based on high-throughput virtual screening strategy, tetrahydrothieno [2,3-c]pyridine scaffold was identified as an initial lead for targeting PAK1. Herein we reported our structure-based optimisation strategy to discover a potent PAK1 inhibitor (7j) which displayed potent PAK1 inhibition and antiproliferatory activity in MDA-MB-231 cells. 7j induced obviously G2/M cell cycle arrest via PAK1-cdc25c-cdc2 pathway, and also inhibited MAPK-ERK and MAPK-JNK cascade to induce MDA-MB-231 cell death. Together, these results provided a novel chemical scaffold as PAK1 inhibitor for breast cancer treatment.
PAK1 inhibitor and synthesis and application thereof in preparation of antitumor drugs
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, (2020/08/09)
The invention relates to a targeted PAK1 inhibitor and an application thereof in preparation of antitumor drugs, and belongs to the technical field of medicines. The structural formula of the compoundor the pharmaceutically acceptable salt thereof is shown in the specification, wherein R1 is a 5-10-membered aryl group or heteroaryl group or a C3-C6 cycloalkyl group, and the 5-10-membered aryl group or heteroaryl group and the C3-C6 cycloalkyl group can be substituted by one or more of the following substituents such as a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkyl groupand a halogen, and R2 is a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a 6-10 membered aryl group, a 5-10 heterocyclic group or heteroaryl group, or a C2-C6 alkenyl group, andthe C1-C6 alkyl group, the 6-10 membered aryl group, the 5-10 heterocyclic group or heteroaryl group, and the C2-C6 alkenyl group can be substituted by one or more halogens. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof can be used as a PAK1 inhibitor for preparing antitumor drugs.
HEARING LOSS-PROTECTIVE COMPOUNDS AND METHODS THEREOF
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Page/Page column 33; 34, (2020/03/02)
Disclosed herein are compounds, and pharmaceutical compositions that include such compounds, for preventing, treating, and/or protecting against sensory hair cell death. Methods of using the compounds, alone or in combination with other therapeutic agents, are also disclosed.
Synthesis and application of novel anti-tumor active compound
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Paragraph 0012; 0013, (2020/04/06)
The invention relates to synthesis and application of a novel anti-tumor active compound, and belongs to the technical field of anti-tumor pharmacy. The technical problem to be solved by the inventionis to provide a compound which is used as an anti-colorectal cancer cell but not limited to a colorectal cancer cell. The compound comprises a compound as shown in the specification or a pharmaceutically acceptable salt thereof. According to the compound or the pharmaceutically acceptable salt thereof, the application is the application of the novel compound in preparation of anti-cancer drugs, and the compound has certain inhibitory activity on tumor cells, especially HCT116 and Hep-G2, so that a new choice is provided for treatment of related tumors. The compound disclosed by the inventionis simple in structure and good in activity, can be used as a leading compound of an anti-cancer drug, and has a good application prospect. The formula I is shown in the specification.
Discovery of a Novel Dual-Target Inhibitor of ERK1 and ERK5 That Induces Regulated Cell Death to Overcome Compensatory Mechanism in Specific Tumor Types
Wang, Guan,Zhao, Yuqian,Liu, Yao,Sun, Dejuan,Zhen, Yongqi,Liu, Jie,Fu, Leilei,Zhang, Lan,Ouyang, Liang
, p. 3976 - 3995 (2020/05/27)
ERK1 and ERK5 are proposed to have pivotal roles in several types of cancer. Under some circumstance, ERK5 may provide a common bypass route, which rescues proliferation upon abrogation of ERK1 signaling. Thus, we accurately classified the tumor types from The Cancer Genome Atlas (TCGA) based on the expression levels of ERK1 and ERK5. We proposed a novel therapeutic strategy to overcome the above-mentioned compensatory mechanism in specific tumor types by co-targeting both ERK1 and ERK5. On the basis of the idea of overcoming ERK5 compensation mechanism, 22ac (ADTL-EI1712) as the first selective dual-target inhibitor of ERK1 and ERK5 was discovered to have potent antitumor effects in vitro and in vivo. Interestingly, this compound was found to induce regulated cell death accompanied by autophagy in MKN-74 cells. Taken together, our results warrant the potential of this dual-target inhibitor as a new candidate drug that conquers compensatory mechanism in certain tumor types.
Discovery of Thieno[2,3- d]pyrimidine-Based Hydroxamic Acid Derivatives as Bromodomain-Containing Protein 4/Histone Deacetylase Dual Inhibitors Induce Autophagic Cell Death in Colorectal Carcinoma Cells
Pan, Zhaoping,Li, Xiang,Wang, Yujia,Jiang, Qinglin,Jiang, Li,Zhang, Min,Zhang, Nan,Wu, Fengbo,Liu, Bo,He, Gu
, p. 3678 - 3700 (2020/04/30)
Bromodomain-containing protein 4 (BRD4) and histone deacetylases (HDAC) are both attractive epigenetic targets in cancer and other chronic diseases. Based on the integrated fragment-based drug design, synthesis, and in vitro and in vivo evaluations, a series of novel thieno[2,3-d]pyrimidine-based hydroxamic acid derivatives are discovered as selective BRD4-HDAC dual inhibitors. Compound 17c is the most potent inhibitor for BRD4 and HDAC with IC50 values at nanomolar levels, as well as the expression level of c-Myc, and increases the acetylation of histone H3. Moreover, 17c presents inhibitory effects on the proliferation of colorectal carcinoma (CRC) cells via inducing autophagic cell death. It also has a good pharmacokinetic profile in rats and oral bioavailability of 40.5%. In the HCT-116 xenograft in vivo models, 17c displays potent inhibitory efficiency on tumor growth by inducing autophagic cell death and suppressing IL6-JAK-STAT signaling pathways. Our results suggest that the BRD4-HDAC dual inhibition might be an attractive therapeutic strategy for CRC.
Thieno quinazolone compound and anti-tumor application thereof
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Paragraph 0013; 0017, (2020/09/23)
The invention relates to thieno quinazolone compounds and application thereof in antitumor drugs, and belongs to the technical field of antitumor pharmacy. The technical problem to be solved by the invention is to provide a compound for resisting colorect
Phenotypic Optimization of Urea-Thiophene Carboxamides to Yield Potent, Well Tolerated, and Orally Active Protective Agents against Aminoglycoside-Induced Hearing Loss
Chowdhury, Sarwat,Owens, Kelly N.,Herr, R. Jason,Jiang, Qin,Chen, Xinchao,Johnson, Graham,Groppi, Vincent E.,Raible, David W.,Rubel, Edwin W,Simon, Julian A.
supporting information, p. 84 - 97 (2018/02/10)
Hearing loss is a major public health concern with no pharmaceutical intervention for hearing protection or restoration. Using zebrafish neuromast hair cells, a robust model for mammalian auditory and vestibular hair cells, we identified a urea-thiophene carboxamide, 1 (ORC-001), as protective against aminoglycoside antibiotic (AGA)-induced hair cell death. The 50% protection (HC50) concentration conferred by 1 is 3.2 μM with protection against 200 μM neomycin approaching 100%. Compound 1 was sufficiently safe and drug-like to validate otoprotection in an in vivo rat hearing loss model. We explored the structure-activity relationship (SAR) of this compound series to improve otoprotective potency, improve pharmacokinetic properties and eliminate off-target activity. We present the optimization of 1 to yield 90 (ORC-13661). Compound 90 protects mechanosensory hair cells with HC50 of 120 nM and demonstrates 100% protection in the zebrafish assay and superior physiochemical, pharmacokinetic, and toxicologic properties, as well as complete in vivo protection in rats.
Design and development of novel Mycobacterium tuberculosis l-alanine dehydrogenase inhibitors
Saxena, Shalini,Samala, Ganesh,Sridevi, Jonnalagadda Padma,Devi, Parthiban Brindha,Yogeeswari, Perumal,Sriram, Dharmarajan
, p. 401 - 414 (2015/03/04)
In the present study, we used crystal structure of MTB L-AlaDH protein complex with N6-methyl adenosine for structure based virtual screening of in house database to identify new small molecule inhibitors for MTB-L-AlaDH. Two molecules identified as better leads and were modified synthetically to obtain thirty novel analogues belonging to 2-iminothiazolidine-4-ones and 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamides. Among the screened compounds four (4n, 4o, 12 and 14) emerged as potent inhibitors displaying IC50 values ranging from 0.58 ± 0.02 to 1.74 ± 0.03 μM against MTB-L-AlaDH and were non-cytotoxic at 50 μM. Some of these synthesized compounds also exhibited good activity against nutrient starved dormant MTB cells. The most potent inhibitors were found to stabilize the protein which was confirmed biophysically through differential scanning fluorimetry.
Development of antimycobacterial tetrahydrothieno[2,3-c]pyridine-3- carboxamides and hexahydrocycloocta[b]thiophene-3-carboxamides: Molecular modification from known antimycobacterial lead
Nallangi, Radhika,Samala, Ganesh,Sridevi, Jonnalagadda Padma,Yogeeswari, Perumal,Sriram, Dharmarajan
, p. 110 - 117 (2014/03/21)
Twenty derivatives of 2,6-disubstituted 4,5,6,7-tetrahydrothieno[2,3-c] pyridine-3-carboxamide and ten of 2-substituted 4,5,6,7,8,9- hexahydrocycloocta[b]thiophene-3-carboxamide were synthesized by molecular modification of a known antimycobacterial molecule. Compounds were evaluated in vitro against Mycobacterium tuberculosis (MTB), and cytotoxicity against RAW 264.7 cell line. Among the compounds, 2-(4-phenoxybenzamido)-4,5,6,7,8,9- hexahydrocycloocta[b]thiophene-3-carboxamide (12f) was found to be the most active compound against MTB with MIC of 3.70 μM and was more potent than Ethambutol (MIC of 7.64 μM), Ciprofloxacin (MIC of 9.41 μM) and standard lead compound SID 92097880 (MIC of 9.15 μM). Compound 12f also showed MTB MIC of 1.23 μM in the presence of an efflux pump inhibitor verapamil, and showed no cytotoxicity at 50 μM.
