Novel Inhibitor-Based Therapies for Thyroid Cancer—An Update

Thyroid cancers (TCs) are the most common tumors of the endocrine system and a constant rise in the number of TC cases has been observed for the past few decades. TCs are one of the most frequent tumors in younger adults, especially in women, therefore early diagnosis and effective therapy are especially important. Ultrasonography examination followed by fine needle biopsy have become the gold standard for diagnosis of TCs, as these strategies allow for early-stage detection and aid accurate qualification for further procedures, including surgical treatment. Despite all the advancements in detection and treatment of TCs, constant mortality levels are still observed. Therefore, a novel generation line of targeted treatment strategies is being developed, including personalized therapies with kinase inhibitors. Recent molecular studies on TCs demonstrate that kinase inhibitor-based therapies might be considered as the most promising. In the past decade, new kinase inhibitors with different mechanisms of action have been reported and approved for clinical trials. This review presents an up-to-date picture of new approaches and challenges of inhibitor-based therapies in treatment of TCs, focusing on the latest findings reported over the past two years.

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Efficient Hit-to-Lead Searching of Kinase Inhibitor Chemical Space via Computational Fragment Merging

10.1101/2021.06.01.446684 ◽

2021 ◽

Author(s):

Grigorii V. Andrianov ◽

Wern Juin Gabriel Ong ◽

Ilya Serebriiskii ◽

John Karanicolas

Keyword(s):

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Chemical Space ◽

Early Stage ◽

Building Blocks ◽

Lead Optimization ◽

Chemical Transformations ◽

Interaction Energies ◽

The Individual ◽

New Compounds

In early stage drug discovery, the stage of hit-to-lead optimization (or "hit expansion") entails starting from a newly-identified active compound, and improving its potency or other properties. Traditionally this process relies on synthesizing and evaluating a series of analogs to build up structure-activity relationships. Here, we describe a computational strategy focused on kinase inhibitors, intended to expedite the process of identifying analogs with improved potency. Our protocol begins from an inhibitor of the target kinase, and generalizes the synthetic route used to access it. By searching for commercially-available replacements for the individual building blocks used to make the parent inhibitor, we compile an enumerated library of compounds that can be accessed using the same chemical transformations; these huge libraries can exceed many millions - or billions - of compounds. Because the resulting libraries are much too large for explicit virtual screening, we instead consider alternate approaches to identify the top-scoring compounds. We find that contributions from individual substituents are well-described by a pairwise additivity approximation, provided that the corresponding fragments position their shared core in precisely the same way relative to the binding site. This key insight allows us to determine which fragments are suitable for merging into a single new compounds, and which are not. Further, the use of the pairwise approximation allows interaction energies to be assigned to each compound in the library, without the need for any further structure-based modeling: interaction energies instead can be reliably estimated from the energies of the component fragments. We demonstrate this protocol using libraries built from five representative kinase inhibitors drawn from the literature, which target four different kinases: CDK9, CHK1, CDK2, and ACK1. In each example, the enumerated library includes additional analogs reported by the original study to have activity, and these analogs are successfully prioritized within the library. We envision that the insights from this work can facilitate the rapid assembly and screening of increasingly large libraries for focused hit-to-lead optimization. To enable adoption of these methods and to encourage further analyses, we disseminate the computational tools needed to deploy this protocol.

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Early Detection is as Important as Imatinib in CML Treatment Success

10.20944/preprints201910.0207.v1 ◽

2019 ◽

Author(s):

Dmitriy Sonkin ◽

Richard Simon

Keyword(s):

Early Detection ◽

Cancer Detection ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Systemic Treatment ◽

Early Cancer ◽

Early Stage ◽

Treatment Success ◽

Myelogenous Leukemia ◽

Clinical Benefits

Chronic myelogenous leukemia (CML) was the first malignancy for which clinical outcome was drastically improved by kinase inhibitor therapy. Kinase inhibitors targeting other well-known oncogenes have been introduced into clinical practice, but none have shown the same magnitude of clinical benefit as ABL1 inhibition in CML. We argue that early detection is an underappreciated, but critically important factor in success of ABL1 inhibitors in treatment of CML. We show that CML provides a window into how many types of cancer may look and behave at an early stage, prior to diagnosis and the development of additional genomic alterations. The remarkable clinical benefits of ABL1 inhibition is likely due to early detection of CML at a stage in which the tumor is driven by single oncogenic alteration which can be successfully controlled by the inhibitor. Thinking of CML as a prototype for effective systemic treatment based on early cancer detection may help to develop strategies for improving treatment for other types of cancer.

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The Pan-PIM Kinase Inhibitor LGB321 Affects Apoptotic Pathways and Microenvironmental Interactions in CLL

Blood ◽

10.1182/blood.v128.22.4370.4370 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4370-4370 ◽

Cited By ~ 1

Author(s):

Sarah Decker ◽

Sandra Kissel ◽

Konrad Aumann ◽

Thorsten Zenz ◽

Katja Zirlik ◽

...

Keyword(s):

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Treatment Strategies ◽

Protective Effects ◽

Effective Treatment Option ◽

Pim Kinases ◽

Cxcr4 Receptor ◽

Nog Mice

Abstract Introduction The emergence of kinase inhibitors like Ibrutinib has drastically altered treatment strategies and improved outcomes in CLL patients, but lack of cure and resistance to therapy still remain serious problems. The three PIM kinases are involved in various important disease mechanisms in CLL, with PIM1 regulating CXCR4 surface expression impacting its interaction with the microenvironment, and PIM2/3 affecting the apoptotic machinery by regulating BAD. The Pan-PIM kinase inhibitor LGB321 (Novartis) targets all three PIM kinases and therefore affects both, CLL apoposis and its interaction with the microenvironment. Results In the study presented here, we investigated the effect of the Pan-PIM kinase inhibitor LGB321 on CLL in vitro and in vivo. LGB321 was highly effective in inducing apoptosis in primary human CLL cells, independent of risk factors or the mutation status. Apoptosis induction correlated with reduced pBAD and BAD levels. LGB321 was also effective in the presence of protective stromal cells and could completely overcome the stroma protective effects. Furthermore, we found that Pan-PIM inhibitor treatment blocked the CXCR4/CXCL12 axis by dephosphorylating the CXCR4 receptor on Ser339, by reducing total CXCR4 protein levels, and by blocking the externalization of the CXCR4 receptor. Concordantly, LGB321 blocked CXCR4 functions like migration towards a CXCL12 gradient (P<.0001), and reduced homing of LGB321-pretreated primary CLL cells towards the bone marrow (P=.0001) of NOG mice. In vivo experiments comfirmed the efficacy of LGB321 in 4 different CLL xenograft studies. Transplantation of primary human CLL cells into NOG mice and treatment with LGB321 for 2 weeks strongly reduced WBC counts, spleen size and spleen infiltration with human CLL cells (P=.0295) in all four CLL cases, and blocked BAD as well as CXCR4 phosphorylation also in vivo. Conclusion Our results demonstrate, that the Pan-PIM kinase inhibitor LGB321 might be an effective treatment option for CLL patients by impairing PIM2/3 mediated CLL-cell survival, and by blocking the PIM1/CXCR4-mediated interaction of CLL cells with their protective microenvironment in vitro and in vivo. Future clinical trials should be performed to validate its efficacy in human CLL. Disclosures Claus: Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria, Other: Travel Funding.

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Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments

Molecules ◽

10.3390/molecules25245949 ◽

2020 ◽

Vol 25 (24) ◽

pp. 5949

Author(s):

Romain Mustière ◽

Patrice Vanelle ◽

Nicolas Primas

Keyword(s):

Recent Progress ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Mechanisms Of Action ◽

Review Of The Literature ◽

Artemisinin Derivatives ◽

Recent Developments ◽

Future Drug ◽

Induce Resistance ◽

Multiple Drugs

Recent progress in reducing malaria cases and ensuing deaths is threatened by factors like mutations that induce resistance to artemisinin derivatives. Multiple drugs are currently in clinical trials for malaria treatment, including some with novel mechanisms of action. One of these, MMV390048, is a plasmodial kinase inhibitor. This review lists the recently developed molecules which target plasmodial kinases. A systematic review of the literature was performed using CAPLUS and MEDLINE databases from 2005 to 2020. It covers a total of 60 articles and describes about one hundred compounds targeting 22 plasmodial kinases. This work highlights the strong potential of compounds targeting plasmodial kinases for future drug therapies. However, the majority of the Plasmodium kinome remains to be explored.

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Changes in ABC Transporter Expression during Hematopoiesis Cause Lineage-Biased Cytopenias in Patients Treated with Aurora Kinase Inhibitors

Blood ◽

10.1182/blood-2021-153422 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4292-4292

Author(s):

Brooke A. Furlong ◽

Ryan R. Posey ◽

David B. Chou ◽

Christos Kyprianou ◽

Lucy R. O'Sullivan ◽

...

Keyword(s):

Board Of Directors ◽

Small Molecule ◽

Abc Transporters ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Early Stage ◽

Aurora Kinase ◽

Advisory Committees ◽

Healthy Human ◽

Aurora Kinase Inhibitors

Abstract Chemotherapy-induced cytopenias are a prevalent and significant issue that worsens clinical outcomes and hinders the effective treatment of cancer. While they are classically associated with traditional cytotoxic chemotherapies, they also occur with newer targeted small molecule drugs and the factors that determine the hematotoxicity profiles of chemotherapies are not fully understood. Here, we explore why Aurora kinase inhibitor drugs cause preferential neutropenia when compared to the cytopenic profiles of targeted small molecule cancer drugs that are FDA approved. By studying drug responses of healthy human hematopoietic cells in vitro and analyzing existing published clinical datasets, we provide evidence that the enhanced vulnerability of neutrophil-lineage cells to Aurora kinase inhibitors is acquired at an early stage of differentiation and is caused by developmental changes in the expression pattern of ATP-binding cassette (ABC) transporters. These data show that hematopoietic cell-intrinsic expression of ABC transporters may be an important factor that determines how some chemotherapies affect the bone marrow. Disclosures David: AstraZeneca: Current Employment. Randle: AstraZeneca: Current Employment. Polanska: AstraZeneca: Current Employment. Urosevic: AstraZeneca: Current Employment. Travers: AstraZeneca: Ended employment in the past 24 months. Ingber: Emulate: Membership on an entity's Board of Directors or advisory committees; BOA Biomedical: Membership on an entity's Board of Directors or advisory committees; Freeflow Medical Devices Inc: Membership on an entity's Board of Directors or advisory committees.

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Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107)

Blood ◽

10.1182/blood-2005-12-010132 ◽

2006 ◽

Vol 108 (4) ◽

pp. 1328-1333 ◽

Cited By ~ 120

Author(s):

Nikolas von Bubnoff ◽

Paul W. Manley ◽

Jurgen Mestan ◽

Jana Sanger ◽

Christian Peschel ◽

...

Keyword(s):

Imatinib Mesylate ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Point Mutations ◽

Treatment Strategies ◽

Kinase Domain ◽

Abl Kinase ◽

Advanced Phase ◽

Clinical Resistance ◽

Limited Spectrum

Abstract In advanced-phase chronic myeloid leukemia (CML), resistance to imatinib mesylate is associated with point mutations in the BCR-ABL kinase domain. A new generation of potent ABL kinase inhibitors is undergoing clinical evaluation. It is important to generate specific resistance profiles for each of these compounds, which could translate into combinatorial and sequential treatment strategies. Having characterized nilotinib (AMN107) against a large panel of imatinib mesylate–resistant Bcr-Abl mutants, we investigated which mutants might arise under nilotinib therapy using a cell-based resistance screen. In contrast to imatinib mesylate, resistance to nilotinib was associated with a limited spectrum of Bcr-Abl kinase mutations. Among these were mutations affecting the P-loop and T315I. Rarely emerging resistant colonies at a concentration of 400 nM nilotinib exclusively expressed the T315I mutation. With the exception of T315I, all of the mutations that were identified were effectively suppressed when the nilotinib concentration was increased to 2000 nM, which falls within the peak-trough range in plasma levels (3.6-1.7 μM) measured in patients treated with 400 mg twice daily. Our findings suggest that nilotinib might be superior to imatinib mesylate in terms of the development of resistance. However, our study indicates that clinical resistance to nilotinib may be associated with the predominant emergence of T315I.

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Cardiovascular care of patients with chronic myeloid leukemia (CML) on tyrosine kinase inhibitor (TKI) therapy

Hematology ◽

10.1182/asheducation-2017.1.110 ◽

2017 ◽

Vol 2017 (1) ◽

pp. 110-114 ◽

Cited By ~ 15

Author(s):

Mary C. Barber ◽

Michael J. Mauro ◽

Javid Moslehi

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Treatment Strategies ◽

Late Toxicity ◽

Patients At Risk ◽

Treatment Free Remission ◽

Cv Disease

Abstract Cardiovascular (CV) health has emerged as an important consideration in patients with chronic myeloid leukemia (CML) because of improved prognosis. Indeed, the success of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has increased the focus on survivorship and late toxicity in oncological care. Survivorship issues in this population include CV disease prevention, given its prevalence in the general population. The introduction of BCR-ABL1 TKIs represented a unique concept of indefinite cancer therapy, only recently evolving to include “treatment-free remission.” Importantly, later-generation BCR-ABL1 TKIs have been associated with CV complications. Dasatinib has been associated with pleural/pericardial effusions and pulmonary hypertension, whereas nilotinib and ponatinib have been linked to the development of vascular occlusive events. There is currently a dearth of data with respect to the mechanisms of drug toxicities, the subsets of patients at risk, and prevention and treatment strategies to mitigate CV complications in patients with CML. Nevertheless, optimal patient CV risk assessment needs to become a more central tenet of patient care in CML. We propose several practical considerations for the practicing oncologist relative to the CV health of patients with CML, especially those on chronic TKI therapy.

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Medical Management of CML

Hematology ◽

10.1182/asheducation-2007.1.371 ◽

2007 ◽

Vol 2007 (1) ◽

pp. 371-375 ◽

Cited By ~ 26

Author(s):

Neil P. Shah

Keyword(s):

Medical Therapy ◽

Progressive Disease ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Management Strategies ◽

Treatment Strategies ◽

Chronic Phase ◽

Abl Kinase ◽

Advanced Phase ◽

Selective Kinase Inhibitor

AbstractManagement strategies of patients with chronic-phase chronic myeloid leukemia (CML) have been revolutionized by the BCR-ABL–selective kinase inhibitor imatinib, which is substantially improving median survival. However, a proportion of patients suffer progressive disease on imatinib therapy. Importantly, patients who are particularly at risk for developing progressive disease can be identified with appropriate monitoring of disease burden. Many of these patients may benefit from alternative treatment strategies, including second-generation kinase inhibitors such as dasatinib. As a result of improvements in medical therapy, allogeneic stem cell transplantation is increasingly deferred despite its known curative potential. It is anticipated that outcomes with medical therapy will continue to improve with the availability of effective second- and third-generation kinase inhibitors, and the percentage of patients progressing to the advanced phase of the disease is projected to decline. The future of kinase inhibitor therapy for CML may involve combinations of ABL kinase inhibitors.

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A Review of Curcumin and Its Derivatives as Anticancer Agents

International Journal of Molecular Sciences ◽

10.3390/ijms20051033 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1033 ◽

Cited By ~ 83

Author(s):

Mhd Tomeh ◽

Roja Hadianamrei ◽

Xiubo Zhao

Keyword(s):

Anticancer Agents ◽

Anticancer Agent ◽

Human Subjects ◽

Curcuma Longa ◽

Treatment Strategies ◽

Mortality Rates ◽

Mechanisms Of Action ◽

Cellular Targets ◽

The Past ◽

Incidence And Mortality

Cancer is the second leading cause of death in the world and one of the major public health problems. Despite the great advances in cancer therapy, the incidence and mortality rates of cancer remain high. Therefore, the quest for more efficient and less toxic cancer treatment strategies is still at the forefront of current research. Curcumin, the active ingredient of the Curcuma longa plant, has received great attention over the past two decades as an antioxidant, anti-inflammatory, and anticancer agent. In this review, a summary of the medicinal chemistry and pharmacology of curcumin and its derivatives in regard to anticancer activity, their main mechanisms of action, and cellular targets has been provided based on the literature data from the experimental and clinical evaluation of curcumin in cancer cell lines, animal models, and human subjects. In addition, the recent advances in the drug delivery systems for curcumin delivery to cancer cells have been highlighted.

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FLT3 and KIT Mutated Pediatric Acute Myeloid Leukemia (AML) Samples Are More Sensitive In Vitro to the Tyrosine Kinase Inhibitor SU11657.

Blood ◽

10.1182/blood.v108.11.1359.1359 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1359-1359

Author(s):

Bianca F. Goemans ◽

Christian M. Zwaan ◽

Desiree de Lange ◽

Jacqueline Cloos ◽

Dirk Reinhardt ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinases ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Treatment Strategies ◽

In Vitro Sensitivity ◽

Study Population ◽

Pediatric Aml ◽

Novel Treatment Strategies

Abstract Novel treatment strategies to improve the outcome of pediatric AML are required. Around 30% of pediatric AML patients harbor a mutation in the tyrosine kinases FLT3 (±20%) or KIT (±10%). Patients with FLT3 and KIT mutations have a poor prognosis. It was reported that FLT3/ITD length and allelic ratio (AR) influence prognosis. Tyrosine kinase inhibitors (TKI) are novel drugs specifically targeting activated tyrosine kinases. SU11657 is a selective TKI of FLT3 and KIT. SU11657 is comparable to SU11248 (sunitinib, Sutent®), which is FDA approved for the treatment op gastro-intestinal stromal tumors (GIST) and renal cell carcinoma. In a phase I trial of sunitinib in AML, all 4 patients with FLT3 mutations had complete (n=1) or partial morphologic responses (n=3) compared with only 20% (2/10) of patients with WT FLT3. All responses were of short duration. In this study we investigated whether pediatric AML samples were sensitive to SU11657 in vitro, and whether sensitivity to SU11657 was related to mutations in FLT3 and KIT. We studied 77 pediatric AML samples for FLT3/ITD, FLT3 D835 and KIT exon 8 and 17 mutations. In case of a FLT3/ITD mutation the ITD length and AR were determined. All 77 samples were also tested for in vitro sensitivity to SU11657 using the 4 day MTT assay (concentration range 0.0098 – 10μM). Two measures of sensitivity were calculated: 1. The LC50 value (the concentration at which 50% of the cells is killed); 2. The percentage of cells surviving (CS) at 0.625 μM SU11657. The study population consisted of 49 boys and 28 girls. Fifty-five samples were taken at initial diagnosis and 22 at relapse. Median age at diagnosis was 9.0 years and median white blood cell count 78.8×109/L. FAB types were M0 5×, M1 9×, M2 11×, M3 3×, M4 21×, M5 14×, M7 2× and unknown 12×. A FLT3/ITD mutation was detected in 22/77 (29%), a FLT3 D835 mutation in 6/71 (8%) and a KIT exon 17 mutation in 4/55 samples (7%). No KIT exon 8 mutations were detected. There was an approximately 1000 fold difference in LC50 values between the most sensitive and most resistant sample to SU11657. WT FLT3 and KIT samples were relatively resistant to SU11657 (median CS at 0.625 μM SU11657=91%). However, FLT3/ITD positive samples were significantly more sensitive to SU11657 [median CS at 0.625 μM=66% (p<0.0001)], as well as the FLT3 D835 mutated samples [median CS at 0.625 μM=64% (p=0.004)]. There was no relation between the AR or ITD length and sensitivity to SU11657 (Spearmans ρ=−0.11 (p=0.7) and −0.04 (p=1.0), respectively). The 4 KIT mutated samples also were significantly more sensitive to SU11657 than WT FLT3 and KIT samples [median CS at 0.625 μM=70% (p=0.049)]. In conclusion, there was large interpatient variation in in vitro sensitivity to SU11657. FLT3 and KIT mutated pediatric AML samples were more sensitive to SU11657 than samples with WT FLT3 and KIT. There was no relation between FLT3/ITD AR or ITD length and sensitivity to SU11657. Further clinical evaluation of SU11657 or sunitinib combined with chemotherapy, would be of interest since a third of pediatric AML patients potentially would be sensitive.

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