scholarly journals MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Arnold Bolomsky ◽  
Meike Vogler ◽  
Murat Cem Köse ◽  
Caroline A. Heckman ◽  
Grégory Ehx ◽  
...  
Keyword(s):  
Development Program ◽  
Myeloid Cell ◽  
Tissue Type ◽  
Special Focus ◽  
Clinical Development Program ◽  
New Class ◽  
Anti Cancer ◽  
Hematological Tumors ◽  
Novel Drug

AbstractCell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis.

scholarly journals Progress in Research on the Role of Flavonoids in Lung Cancer

2019 ◽  
Vol 20 (17) ◽  
pp. 4291 ◽  
Author(s):  
Oana Zanoaga ◽  
Cornelia Braicu ◽  
Ancuta Jurj ◽  
Alexandru Rusu ◽  
Rares Buiga ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Suppressor Genes ◽  
Molecular Mechanisms ◽  
Special Focus ◽  
Physiological Concentration ◽  
Current State ◽  
Anti Cancer ◽  
Molecular Effects ◽  
Lung Cancer Prevention

Lung cancer is the leading cause of cancer deaths worldwide. Therefore, for the prevention, diagnosis, prognosis and treatment of lung cancer, efficient preventive strategies and new therapeutic strategies are needed to face these challenges. Natural bioactive compounds and particular flavonoids compounds have been proven to have an important role in lung cancer prevention and of particular interest is the dose used for these studies, to underline the molecular effects and mechanisms at a physiological concentration. The purpose of this review was to summarize the current state of knowledge regarding relevant molecular mechanisms involved in the pharmacological effects, with a special focus on the anti-cancer role, by regulating the coding and non-coding genes. Furthermore, this review focused on the most commonly altered and most clinically relevant oncogenes and tumor suppressor genes and microRNAs in lung cancer. Particular attention was given to the biological effect in tandem with conventional therapy, emphasizing the role in the regulation of drug resistance related mechanisms.

Differential Role of Components of the Fibrinolytic System in the Formation and Removal of Thrombus Induced by Endothelial Injury

1999 ◽  
Vol 81 (04) ◽  
pp. 601-604 ◽  
Author(s):  
Hiroyuki Matsuno ◽  
Osamu Kozawa ◽  
Masayuki Niwa ◽  
Shigeru Ueshima ◽  
Osamu Matsuo ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Thrombus Formation ◽  
Endothelial Injury ◽  
Fibrinolytic System ◽  
Tissue Type ◽  
Clot Lysis ◽  
Wild Type ◽  
Type Plasminogen Activator ◽  
Pai 1

SummaryThe role of fibrinolytic system components in thrombus formation and removal in vivo was investigated in groups of six mice deficient in urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), or plasminogen activator inhibitor-1 (PAI-1) (u-PA-/-, t-PA-/- or PAI-1-/-, respectively) or of their wild type controls (u-PA+/+, t-PA+/+ or PAI-1+/+). Thrombus was induced in the murine carotid artery by endothelial injury using the photochemical reaction between rose bengal and green light (540 nm). Blood flow was continuously monitored for 90 min on day 0 and for 20 min on days 1, 2 and 3. The times to occlusion after the initiation of endothelial injury in u-PA+/+, t-PA+/+ or PAI-1+/+ mice were 9.4 ± 1.3, 9.8 ± 1.1 or 9.7 ± 1.6 min, respectively. u-PA-/- and t-PA-/- mice were indistinguishable from controls, whereas that of PAI-1-/- mice were significantly prolonged (18.4 ± 3.7 min). Occlusion persisted for the initial 90 min observation period in 10 of 18 wild type mice and was followed by cyclic reflow and reocclusion in the remaining 8 mice. At day 1, persistent occlusion was observed in 1 wild type mouse, 8 mice had cyclic reflow and reocclusion and 9 mice had persistent reflow. At day 2, all injured arteries had persistent reflow. Persistent occlusion for 90 min on day 0 was observed in 3 u-PA-/-, in all t-PA-/- mice at day 1 and in 2 of the t-PA-/-mice at day 2 (p <0.01 versus wild type mice). Persistent patency was observed in all PAI-1-/- mice at day 1 and in 5 of the 6 u-PA-/- mice at day 2 (both p <0.05 versus wild type mice). In conclusion, t-PA increases the rate of clot lysis after endothelial injury, PAI-1 reduces the time to occlusion and delays clot lysis, whereas u-PA has little effect on thrombus formation and spontaneous lysis.

FAITH–BASED COMMUNITIES AND POLITICS IN DULLSTROOM-EMNOTWENI: LOCAL STORIES OF IDENTITY

2016 ◽  
Vol 1 (1) ◽  
pp. 45-57 ◽  
Author(s):  
Christina Landman
Keyword(s):  
Higher Education ◽  
Service Delivery ◽  
Special Focus ◽  
Traditional Role ◽  
Cultural Conflicts ◽  
Local Identities ◽  
Political Interests ◽  
Local Municipality ◽  
The Face

A majority of the black community of Dullstroom-Emnotweni in the Mpumalanga highveld in the east of South Africa trace their descent back to the southern Ndebele of the so-called ‘Mapoch Gronden’, who lost their land in the 1880s to become farm workers on their own land. A hundred years later, in 1980, descendants of the ‘Mapoggers’ settled in the newly built ‘township’ of Dullstroom, called Sakhelwe, finding jobs on the railways or as domestic workers. Oral interviews with the inhabitants of Sakhelwe – a name eventually abandoned in favour of Dullstroom- Emnotweni – testify to histories of transition from landowner to farmworker to unskilled labourer. The stories also highlight cultural conflicts between people of Ndebele, Pedi and Swazi descent and the influence of decades of subordination on local identities. Research projects conducted in this and the wider area of the eMakhazeni Local Municipality reveal the struggle to maintain religious, gender and youth identities in the face of competing political interests. Service delivery, higher education, space for women and the role of faith-based organisations in particular seem to be sites of contestation. Churches and their role in development and transformation, where they compete with political parties and state institutions, are the special focus of this study. They attempt to remain free from party politics, but are nevertheless co-opted into contra-culturing the lack of service delivery, poor standards of higher education and inadequate space for women, which are outside their traditional role of sustaining an oppressed community.

Practical consensus recommendations - Current role of immune response evaluation criteria in solid tumors criteria in the management of cancer patients receiving immunotherapy

2019 ◽  
Vol 4 ◽  
pp. 21-23
Author(s):  
Purvish M. Parikh ◽  
T. P. Sahoo ◽  
Randeep Singh ◽  
Bahl Ankur ◽  
Talvar Vineet ◽  
...  
Keyword(s):  
Immune Response ◽  
Solid Tumors ◽  
Evaluation Criteria ◽  
Supporting Evidence ◽  
Response Evaluation ◽  
Consensus Recommendation ◽  
Current Role ◽  
New Class ◽  
Response Evaluation Criteria

Response evaluation criteria in solid tumors (RECIST) are a method used to evaluate and document the response to cancer treatment in solid tumors. The availability of a new class of immuneoncology drugs has resulted in the need to modify RECIST criteria methodology. The first leadership immuno-oncology network (LION) master course brought together experts in oncology and immuno-oncology. Six questions were put to the experts and their opinion, supporting evidence, and experience were discussed to arrive at a practical consensus recommendation. n this nascent field, the availability of a practical consensus recommendation developed by experts in the field is of immense value to the community oncologist and other health-care consultants.

From Inhibition to Degradation: Targeting the Anti-apoptotic Protein Myeloid Cell Leukemia 1(MCL1)

2019 ◽  
Author(s):  
James Papatzimas ◽  
Evgueni Gorobets ◽  
Ranjan Maity ◽  
Mir Ishruna Muniyat ◽  
Justin L. MacCallum ◽  
...  
Keyword(s):  
Small Molecules ◽  
E3 Ligase ◽  
Myeloid Cell ◽  
Cell Leukemia ◽  
New Class ◽  
Apoptotic Protein ◽  
Family Protein ◽  
Ubiquitination Pathway

<div> <div> <div> <p>Here we show the development of heterobifunctional small molecules capable of selectively targeting MCL1 using a Proteolysis Targeting Chimera (PROTAC) methodology leading to successful degradation. We have confirmed the involvement of the E3 ligase CUL4A-DDB1 cereblon (CRBN) ubiquitination pathway, making these PROTACs a first step toward a new class of anti-apoptotic BCL-2 family protein degraders. </p> </div> </div> </div>

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