The Role of Extrahepatic Metabolism in the Pharmacokinetics of the Targeted Covalent Inhibitors Afatinib, Ibrutinib, and Neratinib

2014 ◽  
Vol 43 (3) ◽  
pp. 375-384 ◽  
Author(s):  
Yoshihiro Shibata ◽  
Masato Chiba
Keyword(s):  
Extrahepatic Metabolism ◽  
Covalent Inhibitors

scholarly journals Targeting KRAS in Lung Cancer Beyond KRAS G12C Inhibitors: The Immune Regulatory Role of KRAS and Novel Therapeutic Strategies

2022 ◽  
Vol 11 ◽  
Author(s):  
Marc Cucurull ◽  
Lucia Notario ◽  
Montse Sanchez-Cespedes ◽  
Cinta Hierro ◽  
Anna Estival ◽  
...  
Keyword(s):  
Tumor Heterogeneity ◽  
Regulatory Role ◽  
Lung Cancers ◽  
Downstream Signaling ◽  
Tumor Immune Microenvironment ◽  
Covalent Inhibitors ◽  
Early Phase Clinical Trials ◽  
Novel Therapeutic Strategies ◽  
Lung Adenocarcinomas

Approximately 20% of lung adenocarcinomas harbor KRAS mutations, an oncogene that drives tumorigenesis and has the ability to alter the immune system and the tumor immune microenvironment. While KRAS was considered “undruggable” for decades, specific KRAS G12C covalent inhibitors have recently emerged, although their promising results are limited to a subset of patients. Several other drugs targeting KRAS activation and downstream signaling pathways are currently under investigation in early-phase clinical trials. In addition, KRAS mutations can co-exist with other mutations in significant genes in cancer (e.g., STK11 and KEAP1) which induces tumor heterogeneity and promotes different responses to therapies. This review describes the molecular characterization of KRAS mutant lung cancers from a biologic perspective to its clinical implications. We aim to summarize the tumor heterogeneity of KRAS mutant lung cancers and its immune-regulatory role, to report the efficacy achieved with current immunotherapies, and to overview the therapeutic approaches targeting KRAS mutations besides KRAS G12C inhibitors.

scholarly journals The ‘aromatic patch’ of three proximal residues in the human acetylcholinesterase active centre allows for versatile interaction modes with inhibitors

1998 ◽  
Vol 335 (1) ◽  
pp. 95-102 ◽  
Author(s):  
Naomi ARIEL ◽  
Arie ORDENTLICH ◽  
Dov BARAK ◽  
Tamar BINO ◽  
Baruch VELAN ◽  
...  
Keyword(s):  
Structural Diversity ◽  
Huperzine A ◽  
Anionic Site ◽  
Active Centre ◽  
Aromatic Residues ◽  
X Ray ◽  
Structural Differences ◽  
Covalent Inhibitors ◽  
Modes Of Interaction

The role of the functional architecture of the human acetylcholinesterase (HuAChE) active centre in accommodating the non-covalent inhibitors tacrine and huperzine A, or the carbamates pyridostigmine and physostigmine, was analysed using 16 mutants of residues lining the active-centre gorge. Despite the structural diversity of the ligands, certain common properties of the complexes could be observed: (a) replacement of aromatic residues Tyr133, Tyr337 and especially Trp86, resulted in pronounced changes in stability of all the complexes examined; (b) effects due to replacements of the five other aromatic residues along the active-centre gorge, such as the acyl pocket (Phe295, Phe297) or at the peripheral anionic site (Tyr124, Trp286, Tyr341) were relatively small; (c) effects due to substitution of the carboxylic residues in the gorge (Glu202, Glu450) were moderate. These results and molecular modelling indicate that the aromatic side chains of residues Trp86, Tyr133 and Tyr337 form together a continuous ‘aromatic patch ’ lining the wall of the active-centre gorge, allowing for the accommodation of the different ligands via multiple modes of interaction. Studies with HuAChE mutants carrying replacements at positions 86, 133 and 337 indicate that the orientations of huperzine A and tacrine in the HuAChE complexes in solution are significantly different from those observed in X-ray structures of the corresponding complexes with Torpedo californica AChE (TcAChE). These discrepancies may be explained in terms of structural differences between the complexes of HuAChE and TcAChE or, more likely, by the enhanced flexibility of the AChE active-centre gorge in solution as compared with the crystalline state.

scholarly journals Concise Chemoenzymatic Total Synthesis and Identification of Cellular Targets of Cepafungin I

2020 ◽  
Author(s):  
Alexander Amatuni ◽  
Anton Shuster ◽  
Alexander Adibekian ◽  
Hans Renata
Keyword(s):  
Total Synthesis ◽  
Natural Product ◽  
Product Family ◽  
Enzymatic Oxidation ◽  
Hydroxyl Group ◽  
Cellular Targets ◽  
Structure Activity ◽  
Covalent Inhibitors

The natural product cepafungin I was recently reported to be one of the most potent covalent inhibitors of the 20S proteasome core particle through a series of in vitro activity assays. Here, we report a short chemoenzymatic total synthesis of cepafungin I featuring the use of a regioselective enzymatic oxidation to prepare a key hydroxylated amino acid building block in a scalable fashion. The strategy developed herein enabled access to a chemoproteomic probe, which in turn revealed the exceptional selectivity and potency of cepafungin I towards the b2 and b5 subunits of the proteasome. Further structure-activity relationship studies suggest the key role of the hydroxyl group in the macrocycle and the identity of the lipid tail in modulating the potency of this natural product family. This study lays the groundwork for further medicinal chemistry exploration to fully realize the anticancer potential of cepafungin I. <br>

scholarly journals Optimization and Anti-Cancer Properties of Fluoromethylketones as Covalent Inhibitors for Ubiquitin C-Terminal Hydrolase L1

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1227
Author(s):  
Aaron D. Krabill ◽  
Hao Chen ◽  
Sajjad Hussain ◽  
Chad S. Hewitt ◽  
Ryan D. Imhoff ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Deubiquitinating Enzyme ◽  
Migration Behavior ◽  
Disease States ◽  
Ic50 Value ◽  
Anti Cancer ◽  
Covalent Inhibitors ◽  
And Migration ◽  
First Time

The deubiquitinating enzyme (DUB) UCHL1 is implicated in various disease states including neurodegenerative disease and cancer. However, there is a lack of quality probe molecules to gain a better understanding on UCHL1 biology. To this end a study was carried out to fully characterize and optimize the irreversible covalent UCHL1 inhibitor VAEFMK. Structure-activity relationship studies identified modifications to improve activity versus the target and a full cellular characterization was carried out for the first time with this scaffold. The studies produced a new inhibitor, 34, with an IC50 value of 7.7 µM against UCHL1 and no observable activity versus the closest related DUB UCHL3. The molecule was also capable of selectively inhibiting UCHL1 in cells and did not demonstrate any discernible off-target toxicity. Finally, the molecule was used for initial probe studies to assess the role of UCHL1 role in proliferation of myeloma cells and migration behavior in small cell lung cancer cells making 34 a new tool to be used in the biological evaluation of UCHL1.

scholarly journals Concise Chemoenzymatic Total Synthesis and Identification of Cellular Targets of Cepafungin I

2020 ◽  
Author(s):  
Alexander Amatuni ◽  
Anton Shuster ◽  
Alexander Adibekian ◽  
Hans Renata
Keyword(s):  
Total Synthesis ◽  
Natural Product ◽  
Product Family ◽  
Enzymatic Oxidation ◽  
Hydroxyl Group ◽  
Cellular Targets ◽  
Structure Activity ◽  
Covalent Inhibitors

The natural product cepafungin I was recently reported to be one of the most potent covalent inhibitors of the 20S proteasome core particle through a series of in vitro activity assays. Here, we report a short chemoenzymatic total synthesis of cepafungin I featuring the use of a regioselective enzymatic oxidation to prepare a key hydroxylated amino acid building block in a scalable fashion. The strategy developed herein enabled access to a chemoproteomic probe, which in turn revealed the exceptional selectivity and potency of cepafungin I towards the b2 and b5 subunits of the proteasome. Further structure-activity relationship studies suggest the key role of the hydroxyl group in the macrocycle and the identity of the lipid tail in modulating the potency of this natural product family. This study lays the groundwork for further medicinal chemistry exploration to fully realize the anticancer potential of cepafungin I. <br>

Role of dactinomycin in the improved survival of children with Wilms' tumor

JAMA ◽  
1966 ◽  
Vol 195 (12) ◽  
pp. 1005-1009 ◽  
Author(s):  
D. J. Fernbach
Keyword(s):  
Wilms Tumor

Role of the allergist in diagnosis and management of patients with uveitis

JAMA ◽  
1966 ◽  
Vol 195 (3) ◽  
pp. 167-172 ◽  
Author(s):  
T. E. Van Metre
Keyword(s):  
Diagnosis And Management

The power of norms to sway fused group members

2018 ◽  
Vol 41 ◽  
Author(s):  
Winnifred R. Louis ◽  
Craig McGarty ◽  
Emma F. Thomas ◽  
Catherine E. Amiot ◽  
Fathali M. Moghaddam
Keyword(s):  
Evolutionary Anthropology ◽  
Normative Systems ◽  
Violent Extremism ◽  
Identity Fusion ◽  
Group Members

AbstractWhitehouse adapts insights from evolutionary anthropology to interpret extreme self-sacrifice through the concept of identity fusion. The model neglects the role of normative systems in shaping behaviors, especially in relation to violent extremism. In peaceful groups, increasing fusion will actually decrease extremism. Groups collectively appraise threats and opportunities, actively debate action options, and rarely choose violence toward self or others.

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