scholarly journals An Update on Development of Small-Molecule Plasmodial Kinase Inhibitors

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5182
Author(s):  
Chantalle Moolman ◽  
Rencia van der Sluis ◽  
Richard M. Beteck ◽  
Lesetja J. Legoabe
Keyword(s):  
Small Molecule ◽  
Antimalarial Drug ◽  
Kinase Inhibitors ◽  
Antimalarial Drugs ◽  
Next Generation ◽  
Antimalarial Drug Resistance ◽  
Cellular Processes ◽  
Antimalarial Agents ◽  
Molecule Inhibitor ◽  
Multiple Stages

Malaria control relies heavily on the small number of existing antimalarial drugs. However, recurring antimalarial drug resistance necessitates the continual generation of new antimalarial drugs with novel modes of action. In order to shift the focus from only controlling this disease towards elimination and eradication, next-generation antimalarial agents need to address the gaps in the malaria drug arsenal. This includes developing drugs for chemoprotection, treating severe malaria and blocking transmission. Plasmodial kinases are promising targets for next-generation antimalarial drug development as they mediate critical cellular processes and some are active across multiple stages of the parasite’s life cycle. This review gives an update on the progress made thus far with regards to plasmodial kinase small-molecule inhibitor development.

scholarly journals CDK10 in Gastrointestinal Cancers: Dual Roles as a Tumor Suppressor and Oncogene

2021 ◽  
Vol 11 ◽  
Author(s):  
Zainab A. Bazzi ◽  
Isabella T. Tai
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Small Molecule ◽  
High Throughput Screening ◽  
Kinase Activity ◽  
Screening Assay ◽  
Cellular Processes ◽  
Molecule Inhibitor ◽  
High Throughput Screening Assay ◽  
Kinase Activity Assay

Cyclin-dependent kinase 10 (CDK10) is a CDC2-related serine/threonine kinase involved in cellular processes including cell proliferation, transcription regulation and cell cycle regulation. CDK10 has been identified as both a candidate tumor suppressor in hepatocellular carcinoma, biliary tract cancers and gastric cancer, and a candidate oncogene in colorectal cancer (CRC). CDK10 has been shown to be specifically involved in modulating cancer cell proliferation, motility and chemosensitivity. Specifically, in CRC, it may represent a viable biomarker and target for chemoresistance. The development of therapeutics targeting CDK10 has been hindered by lack a specific small molecule inhibitor for CDK10 kinase activity, due to a lack of a high throughput screening assay. Recently, a novel CDK10 kinase activity assay has been developed, which will aid in the development of small molecule inhibitors targeting CDK10 activity. Discovery of a small molecular inhibitor for CDK10 would facilitate further exploration of its biological functions and affirm its candidacy as a therapeutic target, specifically for CRC.

scholarly journals Comparison of Efficacies of Cysteine Protease Inhibitors against Five Strains of Plasmodium falciparum

2001 ◽  
Vol 45 (3) ◽  
pp. 949-951 ◽  
Author(s):  
Ajay Singh ◽  
Philip J. Rosenthal
Keyword(s):  
Plasmodium Falciparum ◽  
Protease Inhibitors ◽  
Cysteine Protease ◽  
Antimalarial Drug ◽  
Drug Target ◽  
Antimalarial Drugs ◽  
Cross Resistance ◽  
Cysteine Protease Inhibitors ◽  
Antimalarial Agents ◽  
Parasite Strains

ABSTRACT Falcipain-2, a cysteine protease and essential hemoglobinase ofPlasmodium falciparum, is a potential antimalarial drug target. We compared the falcipain-2 sequences and sensitivities to cysteine protease inhibitors of five parasite strains that differ markedly in sensitivity to established antimalarial drugs. The sequence of falcipain-2 was highly conserved, and the sensitivities of all of the strains to falcipain-2 inhibitors were very similar. Thus, cross-resistance between cysteine protease inhibitors and other antimalarial agents is not expected in parasites that are now circulating and falcipain-2 remains a promising chemotherapeutic target.

scholarly journals Role ofPfmdr1inIn VitroPlasmodium falciparum Susceptibility to Chloroquine, Quinine, Monodesethylamodiaquine, Mefloquine, Lumefantrine, and Dihydroartemisinin

2014 ◽  
Vol 58 (12) ◽  
pp. 7032-7040 ◽  
Author(s):  
Nathalie Wurtz ◽  
Bécaye Fall ◽  
Aurélie Pascual ◽  
Mansour Fall ◽  
Eric Baret ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Antimalarial Drug ◽  
Antimalarial Drugs ◽  
Wild Type ◽  
Antimalarial Drug Resistance ◽  
Content Type ◽  
Increased Susceptibility

ABSTRACTThe involvement ofPfmdr1(Plasmodium falciparummultidrug resistance 1) polymorphisms in antimalarial drug resistance is still debated. Here, we evaluate the association between polymorphisms inPfmdr1(N86Y, Y184F, S1034C, N1042D, and D1246Y) andPfcrt(K76T) andin vitroresponses to chloroquine (CQ), mefloquine (MQ), lumefantrine (LMF), quinine (QN), monodesethylamodiaquine (MDAQ), and dihydroartemisinin (DHA) in 174Plasmodium falciparumisolates from Dakar, Senegal. ThePfmdr186Y mutation was identified in 14.9% of the samples, and the 184F mutation was identified in 71.8% of the isolates. No 1034C, 1042N, or 1246Y mutations were detected. ThePfmdr186Y mutation was significantly associated with increased susceptibility to MDAQ (P= 0.0023), LMF (P= 0.0001), DHA (P= 0.0387), and MQ (P= 0.00002). The N86Y mutation was not associated with CQ (P= 0.214) or QN (P= 0.287) responses. ThePfmdr1184F mutation was not associated with various susceptibility responses to the 6 antimalarial drugs (P= 0.168 for CQ, 0.778 for MDAQ, 0.324 for LMF, 0.961 for DHA, 0.084 for QN, and 0.298 for MQ). ThePfmdr186Y-Y184 haplotype was significantly associated with increased susceptibility to MDAQ (P= 0.0136), LMF (P= 0.0019), and MQ (P= 0.0001). The additionalPfmdr186Y mutation increased significantly thein vitrosusceptibility to MDAQ (P< 0.0001), LMF (P< 0.0001), MQ (P< 0.0001), and QN (P= 0.0026) in wild-typePfcrtK76 parasites. The additionalPfmdr186Y mutation significantly increased thein vitrosusceptibility to CQ (P= 0.0179) inPfcrt76T CQ-resistant parasites.

scholarly journals Small-Molecule Inhibitor Targeting Protein Kinase D: A Potential Therapeutic Strategy

2021 ◽  
Vol 11 ◽  
Author(s):  
Die Lv ◽  
Hongli Chen ◽  
Yun Feng ◽  
Bomiao Cui ◽  
Yingzhu Kang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Small Molecule ◽  
Therapeutic Strategy ◽  
Protein Kinase D ◽  
Successful Development ◽  
Cellular Processes ◽  
The Past ◽  
Calcium Calmodulin Dependent ◽  
Pathological Conditions ◽  
Molecule Inhibitor

The protein kinase D (PKD) family is a family of serine-threonine kinases that are members of the calcium/calmodulin-dependent kinase (CaMK) superfamily. PKDs have been increasingly implicated in multiple pivotal cellular processes and pathological conditions. PKD dysregulation is associated with several diseases, including cancer, inflammation, and obesity. Over the past few years, small-molecule inhibitors have emerged as alternative targeted therapy with fewer adverse side effects than currently available chemotherapy, and these specifically targeted inhibitors limit non-specific toxicities. The successful development of PKD inhibitors would significantly suppress the growth and proliferation of various cancers and inhibit the progression of other diseases. Various PKD inhibitors have been studied in the preclinical setting. In this context, we summarize the PKD inhibitors under investigation and their application for different kinds of diseases.

Recent advances in the development of chemotherapeutic agents for malaria.

2020 ◽  
Vol 21 ◽  
Author(s):  
Neelima Shrivastava ◽  
Shah A. Khan ◽  
Saif Ahmad ◽  
Khalid Al Balushi ◽  
Asif Husain
Keyword(s):  
Antimalarial Drug ◽  
Hybrid Approach ◽  
Public Health Problem ◽  
Antimalarial Drugs ◽  
Chemotherapeutic Agents ◽  
World Health ◽  
Major Public Health Problem ◽  
Antimalarial Agents ◽  
Recent Advances ◽  
Made In

Introduction: Malaria, a devastating infectious parasitic disease, has been recognized by the World Health organization (WHO) as a major public health problem worldwide. It is one of the leading causes of morbidity and mortality in the developing countries. There are fewer number of the antimalarial drugs available in the market to combat this deadly disease. The situation is further worsened due to the emergence of resistant strains of Plasmodium falciparum, which warrants the search for novel antimalarial drugs capable of acting at multiple targets to expand the current antimalarial drug arsenal for better therapeutic outcome. Objectives: This review aimed to provide the reader with the recent advances and progress made in the development of chemotherapeutic agents for malaria. Methods: Literature review data on chemistry and antimalarial activity of natural and synthetic heterocyclic compounds published in the last ten years were compiled by referring various peer reviewed journal websites and medical search engines. Results and discussion: This review is covers the recent advances and progress made in the treatment strategies, patent granted, synthetic approaches, mechanism of action with more emphasis on structure activity relationship (SAR) of potential chemotherapeutic agents as antimalarial agents which could pave the way for the development of more effective and potent antimalarial agents. This review might interest the fellow researchers working on the development of novel antimalarial drug candidates with better therapeutic index. Conclusion: Based on the literature covered in the current review article and seeing the recent trends, authors are of the opinion that the multi target conjugated hybrid approach is the best strategy to discover and develop the effective antimalarial agents.

scholarly journals A novel fusion of RBM6 to CSF1R in acute megakaryoblastic leukemia

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 323-333 ◽  
Author(s):  
Ting-lei Gu ◽  
Thomas Mercher ◽  
Jeffrey W. Tyner ◽  
Valerie L. Goss ◽  
Denise K. Walters ◽  
...  
Keyword(s):  
Small Molecule ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Rna Binding ◽  
Binding Motif ◽  
Acute Megakaryoblastic Leukemia ◽  
Growth And Survival ◽  
Megakaryoblastic Leukemia ◽  
Large Numbers ◽  
Molecule Inhibitor

Activated tyrosine kinases have been frequently implicated in the pathogenesis of cancer, including acute myeloid leukemia (AML), and are validated targets for therapeutic intervention with small-molecule kinase inhibitors. To identify novel activated tyrosine kinases in AML, we used a discovery platform consisting of immunoaffinity profiling coupled to mass spectrometry that identifies large numbers of tyrosine-phosphorylated proteins, including active kinases. This method revealed the presence of an activated colony-stimulating factor 1 receptor (CSF1R) kinase in the acute megakaryoblastic leukemia (AMKL) cell line MKPL-1. Further studies using siRNA and a small-molecule inhibitor showed that CSF1R is essential for the growth and survival of MKPL-1 cells. DNA sequence analysis of cDNA generated by 5′RACE from CSF1R coding sequences identified a novel fusion of the RNA binding motif 6 (RBM6) gene to CSF1R gene generated presumably by a t(3;5)(p21;q33) translocation. Expression of the RBM6-CSF1R fusion protein conferred interleukin-3 (IL-3)–independent growth in BaF3 cells, and induces a myeloid proliferative disease (MPD) with features of megakaryoblastic leukemia in a murine transplant model. These findings identify a novel potential therapeutic target in leukemogenesis, and demonstrate the utility of phosphoproteomic strategies for discovery of tyrosine kinase alleles.

scholarly journals Antimalarial Drug Resistance Profiling of Plasmodium falciparum Infections in Ghana Using Molecular Inversion Probes and Next-Generation Sequencing

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Benedicta A. Mensah ◽  
Ozkan Aydemir ◽  
James L. Myers-Hansen ◽  
Millicent Opoku ◽  
Nicholas J. Hathaway ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Next Generation Sequencing ◽  
Antimalarial Drug ◽  
Next Generation ◽  
Cape Coast ◽  
Antimalarial Drug Resistance ◽  
Content Type ◽  
Molecular Inversion Probes ◽  
Generation Sequencing

ABSTRACT A key drawback to monitoring the emergence and spread of antimalarial drug resistance in sub-Saharan Africa is early detection and containment. Next-generation sequencing methods offer the resolution, sensitivity, and scale required to fill this gap by surveilling for molecular markers of drug resistance. We performed targeted sequencing using molecular inversion probes to interrogate five Plasmodium falciparum genes (pfcrt, pfmdr1, pfdhps, pfdhfr, and pfk13) implicated in chloroquine, sulfadoxine-pyrimethamine (SP), and artemisinin resistance in two sites in Ghana. A total of 803 dried blood spots from children aged between 6 months and 14 years presenting with uncomplicated P. falciparum malaria at the Begoro District Hospital in Begoro and the Ewim Polyclinic in Cape Coast, Ghana, from 2014 to 2017 were prepared on filter paper. Thirteen years after the removal of drug pressure, chloroquine-sensitive parasite strains with pfcrt K76 have increased nearly to fixation in Begoro, in the forest area (prevalence = 95%), but at a lower rate in Cape Coast, in the coastal region (prevalence = 71%, Z = −3.5, P < 0.001). In addition, pfmdr1 184F-bearing parasites are under strong selection. The pfdhfr/pfdhps quadruple genotype (IRNGK), associated with SP resistance, is near saturation. Our study identified at a 2 to 10% prevalence pfdhps 581G, which is a sulfadoxine resistance marker that correlates with the failure of SP prophylaxis in pregnancy and which has not been observed in Ghana. The differences in the reexpansion of chloroquine-sensitive strains observed at the two study sites, the stronger SP resistance, and the high prevalence of pfmdr1 184F should be further monitored to inform malaria control strategies in Ghana.

Detection of antimalarial drug resistance polymorphisms in Plasmodium falciparum chloroquine resistance transporter and Plasmodium falciparum multidrug resistance 1 genes of Plasmodium falciparum found in Kano State, Nigeria

2021 ◽  
Vol 5 ◽  
pp. 8-14
Author(s):  
Al-Mukhtar Yahuza Adamu ◽  
Olayeni Stephen Olonitola ◽  
Helen Ileigo Inabo ◽  
Ahmad Babangida Suleiman
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Antimalarial Drug ◽  
Artemisinin Combination Therapy ◽  
Chloroquine Resistance ◽  
Antimalarial Drug Resistance ◽  
Antimalarial Agents ◽  
Chloroquine Resistance Transporter ◽  
Two Samples

Objectives: In 2018, malaria claimed an estimated 380,000 lives in African region, with Nigeria accounting for 24.0% (91,368) of malaria deaths from the region. Mutations in Plasmodium falciparum chloroquine resistance transporter (Pfcrt) and P. falciparum multidrug resistance 1 (Pfmdr-1) genes had reduced the effective use of artemisinin combination therapy through the development of resistance to these antimalarial agents. Our study set out to determine the antimalarial drug resistance polymorphisms in Pfcrt and Pfmdr-1 genes of P. falciparum isolates among patients in Kano State, Nigeria. Material and Methods: Malaria positive samples were collected across the three senatorial districts of Kano State. The samples were amplified using nested polymerase chain reaction to detect the Pfcrt and Pfmdr-1 genes. The amplicons were sequenced and bioinformatic analysis was done using CLC Sequence viewer 8.0 and BioEdit sequence alignment editor to detect the single-nucleotide polymorphisms. Results: In the Pfcrt gene, CVIET haplotype was seen in 26.2% of the samples while only two samples showed the 86Y mutation in the Pfmdr-1 gene. All the 86Y mutations and majority of the CVIET haplotypes were detected in the patients from rural settings where some of them noted that they consumed modern and traditional (herbs) antimalarial agents. One sample was observed to have the CVIET haplotype and N86Y mutation while the other five CVIET haplotypes were seen in five separate samples. A new mutation V62A was found in the Pfmdr-1 gene as observed in one of the sample. Conclusion: It is imperative to ensure the rational use of the right antimalarial agents and employ continuous resistance surveillance/mapping to ensure synergy in malaria containment and elimination strategies.

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