Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed ...towards identification and development of pharmaceutical CDK inhibitors. Insights into the biological consequences of CDK inhibition in specific tumor types have led to the successful development of CDK4/6 inhibitors as treatments for certain types of breast cancer. More recently, a new generation of pharmaceutical inhibitors of CDK enzymes that regulate the transcription of key oncogenic and pro-survival proteins, including CDK9, have entered clinical development. Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of seliciclib. We describe its synthesis and mechanistic characterization. Fadraciclib exhibits improved potency and selectivity for CDK2 and CDK9 compared to seliciclib, and also displays high selectivity across the kinome. We show that the mechanism of action of fadraciclib is consistent with potent inhibition of CDK9-mediated transcription, decreasing levels of RNA polymerase II C-terminal domain serine 2 phosphorylation, the pro-survival protein Myeloid Cell Leukemia 1 (MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells. This cellular potency and mechanism of action translate to promising anti-cancer activity in human leukemia mouse xenograft models. Studies of leukemia cell line sensitivity identify mixed lineage leukemia (MLL) gene status and the level of B-cell lymphoma 2 (BCL2) family proteins as potential markers for selection of patients with greater sensitivity to fadraciclib. We show that the combination of fadraciclib with BCL2 inhibitors, including venetoclax, is synergistic in leukemic cell models, as predicted from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9- or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors (NCT02552953) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) (NCT03739554) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (NCT04017546).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Over the past two decades there has been a great deal of interest in the development of inhibitors of the cyclin-dependent kinases (CDKs). This attention initially stemmed from observations that ...different CDK isoforms have key roles in cancer cell proliferation through loss of regulation of the cell cycle, a hallmark feature of cancer. CDKs have now been shown to regulate other processes, particularly various aspects of transcription. The early non-selective CDK inhibitors exhibited considerable toxicity and proved to be insufficiently active in most cancers. The lack of patient selection biomarkers and an absence of understanding of the inhibitory profile required for efficacy hampered the development of these inhibitors. However, the advent of potent isoform-selective inhibitors with accompanying biomarkers has re-ignited interest. Palbociclib, a selective CDK4/6 inhibitor, is now approved for the treatment of ER+/HER2- advanced breast cancer. Current developments in the field include the identification of potent and selective inhibitors of the transcriptional CDKs; these include tool compounds that have allowed exploration of individual CDKs as cancer targets and the determination of their potential therapeutic windows. Biomarkers that allow the selection of patients likely to respond are now being discovered. Drug resistance has emerged as a major hurdle in the clinic for most protein kinase inhibitors and resistance mechanism are beginning to be identified for CDK inhibitors. This suggests that the selective inhibitors may be best used combined with standard of care or other molecularly targeted agents now in development rather than in isolation as monotherapies.
The discovery and development of small molecule cancer drugs has been revolutionised over the last decade. Most notably, we have moved from a one-size-fits-all approach that emphasized cytotoxic ...chemotherapy to a personalised medicine strategy that focuses on the discovery and development of molecularly targeted drugs that exploit the particular genetic addictions, dependencies and vulnerabilities of cancer cells. These exploitable characteristics are increasingly being revealed by our expanding understanding of the abnormal biology and genetics of cancer cells, accelerated by cancer genome sequencing and other high-throughput genome-wide campaigns, including functional screens using RNA interference. In this review we provide an overview of contemporary approaches to the discovery of small molecule cancer drugs, highlighting successes, current challenges and future opportunities. We focus in particular on four key steps: Target validation and selection; chemical hit and lead generation; lead optimization to identify a clinical drug candidate; and finally hypothesis-driven, biomarker-led clinical trials. Although all of these steps are critical, we view target validation and selection and the conduct of biology-directed clinical trials as especially important areas upon which to focus to speed progress from gene to drug and to reduce the unacceptably high attrition rate during clinical development. Other challenges include expanding the envelope of druggability for less tractable targets, understanding and overcoming drug resistance, and designing intelligent and effective drug combinations. We discuss not only scientific and technical challenges, but also the assessment and mitigation of risks as well as organizational, cultural and funding problems for cancer drug discovery and development, together with solutions to overcome the ‘Valley of Death’ between basic research and approved medicines. We envisage a future in which addressing these challenges will enhance our rapid progress towards truly personalised medicine for cancer patients.
► Here we review small molecule cancer drug discovery and development. ► We focus on Target selection, hit identification, lead optimization and clinical trials. ► A particular emphasis of this article is personalized medicine.
Highlights • PI3K is an important target for innovative anticancer drug development and precision medicine. • Over 30 small molecule PI3K inhibitors are currently in clinical trial testing. • These ...drugs include dual PI3K/mTOR, pan-Class I PI3K and isoform-selective PI3K inhibitors. • The PI3Kδ inhibitor idelalisib has received FDA approval for the treatment of B-cell malignancies. • Drug resistance, patient selection and development of targeted combinations remain challenges.
This review focuses on the methodology used for the construction of tetrahydropyran (THP) rings in the synthesis of natural products over the last seven years. While methods like cyclisation onto ...oxocarbenium ions, reduction of cyclic hemi-ketals, Michael reactions, hetero-Diels-Alder cycloadditions and cyclisations onto epoxides continue to find application, several other strategies including metal-mediated cyclisations, ring-closing metathesis, radical cyclisations and carbocation cyclisations have also found use. This review is intended to provide an overview of the area for those who are unfamiliar, and to refresh and remind those who do work in the area of the exciting developments in the field.
This paper reports an investigation into organocatalytic hydrogels as prebiotically relevant systems. Gels are interesting prebiotic reaction media, combining heterogeneous and homogeneous ...characteristics with a structurally organized active “solid-like” catalyst separated from the surrounding environment, yet in intimate contact with the solution phase and readily accessible via “liquid-like” diffusion. A simple self-assembling glutamine amide derivative 1 was initially found to catalyze a model aldol reaction between cyclohexanone and 4-nitrobenzaldehyde, but it did not maintain its gel structure during reaction. In this study, it was observed that compound 1 could react directly with the benzaldehyde to form a hydrogel in situ based on Schiff base 2 as a low-molecular-weight gelator (LMWG). This new dynamic gel is a rare example of a two-component self-assembled LMWG hydrogel and was fully characterized. It was demonstrated that glutamine amide 1 could select an optimal aldehyde component and preferentially assemble from mixtures. In the hunt for an organocatalyst, reductive conditions were applied to the Schiff base to yield secondary amine 3, which is also a highly effective hydrogelator at very low loadings with a high degree of nanoscale order. Most importantly, the hydrogel based on 3 catalyzed the prebiotically relevant aldol dimerization of glycolaldehyde to give threose and erythrose. In buffered conditions, this reaction gave excellent conversions, good diastereoselectivity, and some enantioselectivity. Catalysis using the hydrogel of 3 was much better than that using non-assembled 3demonstrating a clear benefit of self-assembly. The results suggest that hydrogels offer a potential strategy by which prebiotic reactions can be promoted using simple, prebiotically plausible LMWGs that can selectively self-organize from complex mixtures. Such processes may have been of prebiotic importance.
Histone deacetylase inhibitors (HDACi) comprise structurally diverse compounds that are a group of targeted anticancer agents.
The first of these new HDACi, vorinostat (suberoylanilide hydroxamic ...acid), has received Food and Drug Administration approval
for treating patients with cutaneous T-cell lymphoma. This review focuses on the activities of the 11 zinc-containing HDACs,
their histone and nonhistone protein substrates, and the different pathways by which HDACi induce transformed cell death.
A hypothesis is presented to explain the relative resistance of normal cells to HDACi-induced cell death. (Mol Cancer Res
2007;5(10):981–9)
Heat-shock protein 70 (HSP70) isoforms contribute to tumorigenesis through their well-documented antiapoptotic activity and via their role as cochaperones for the HSP90 molecular chaperone. HSP70 ...expression is induced following treatment with HSP90 inhibitors, which may attenuate the cell death effects of this class of inhibitor. Here we show that silencing either heat-shock cognate 70 (HSC70) or HSP72 expression in human cancer cell lines has no effect on HSP90 activity or cell proliferation. However, simultaneously reducing the expression of both of these isoforms induces proteasome-dependent degradation of HSP90 client proteins, G1 cell-cycle arrest, and extensive tumor-specific apoptosis. Importantly, simultaneous silencing of HSP70 isoforms in nontumorigenic cell lines does not result in comparable growth arrest or induction of apoptosis, indicating a potential therapeutic window.
The development of an asymmetric "clip-cycle" synthesis of 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines, which are increasingly important scaffolds in drug discovery programs, is ...reported. Cbz-protected bis-homoallylic amines were activated by "clipping" them to thioacrylate via an alkene metathesis reaction. Enantioselective intramolecular aza-Michael cyclization onto the activated alkene, catalyzed by a chiral phosphoric acid, formed a pyrrolidine. The reaction accommodated a range of substitutions to form 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines with high enantioselectivities. The importance of the thioester activating group was demonstrated by comparison to ketone and oxoester-containing substrates. DFT studies supported the aza-Michael cyclization as the rate- and stereochemistry-determining step and correctly predicted the formation of the major enantiomer. The catalytic asymmetric syntheses of
-methylpyrrolidine alkaloids (
)-irnidine and (
)-bgugaine, which possess DNA binding and antibacterial properties, were achieved using the "clip-cycle" methodology.
Protein kinase clients are recruited to the Hsp90 molecular chaperone system via Cdc37, which simultaneously binds Hsp90 and kinases and regulates the Hsp90 chaperone cycle. Pharmacological ...inhibition of Hsp90 in vivo results in degradation of kinase clients, with a therapeutic effect in dependent tumors. We show here that Cdc37 directly antagonizes ATP binding to client kinases, suggesting a role for the Hsp90-Cdc37 complex in controlling kinase activity. Unexpectedly, we find that Cdc37 binding to protein kinases is itself antagonized by ATP-competitive kinase inhibitors, including vemurafenib and lapatinib. In cancer cells, these inhibitors deprive oncogenic kinases such as B-Raf and ErbB2 of access to the Hsp90-Cdc37 complex, leading to their degradation. Our results suggest that at least part of the efficacy of ATP-competitive inhibitors of Hsp90-dependent kinases in tumor cells may be due to targeted chaperone deprivation.
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