Kinase inhibitors: the road ahead
TL;DR: An overview of the novel targets, biological processes and disease areas that kinase-targeting small molecules are being developed against, highlight the associated challenges and assess the strategies and technologies that are enabling efficient generation of highly optimized kinase inhibitors are provided.
Abstract: Receptor tyrosine kinase signalling pathways have been successfully targeted to inhibit proliferation and angiogenesis for cancer therapy. However, kinase deregulation has been firmly demonstrated to play an essential role in virtually all major disease areas. Kinase inhibitor drug discovery programmes have recently broadened their focus to include an expanded range of kinase targets and therapeutic areas. In this Review, we provide an overview of the novel targets, biological processes and disease areas that kinase-targeting small molecules are being developed against, highlight the associated challenges and assess the strategies and technologies that are enabling efficient generation of highly optimized kinase inhibitors.
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01 Aug 2001
TL;DR: The study of distributed systems which bring to life the vision of ubiquitous computing systems, also known as ambient intelligence, is concentrated on in this work.
Abstract: With digital equipment becoming increasingly networked, either on wired or wireless networks, for personal and professional use alike, distributed software systems have become a crucial element in information and communications technologies. The study of these systems forms the core of the ARLES' work, which is specifically concerned with defining new system software architectures, based on the use of emerging networking technologies. In this context, we concentrate on the study of distributed systems which bring to life the vision of ubiquitous computing systems, also known as ambient intelligence.
2,774 citations
TL;DR: Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, they are still able to identify only two de novo combinatorials compounds approved as drugs in this 39-year time frame.
Abstract: This review is an updated and expanded version of the five prior reviews that were published in this journal in 1997, 2003, 2007, 2012, and 2016. For all approved therapeutic agents, the time frame has been extended to cover the almost 39 years from the first of January 1981 to the 30th of September 2019 for all diseases worldwide and from ∼1946 (earliest so far identified) to the 30th of September 2019 for all approved antitumor drugs worldwide. As in earlier reviews, only the first approval of any drug is counted, irrespective of how many "biosimilars" or added approvals were subsequently identified. As in the 2012 and 2016 reviews, we have continued to utilize our secondary subdivision of a "natural product mimic", or "NM", to join the original primary divisions, and the designation "natural product botanical", or "NB", to cover those botanical "defined mixtures" now recognized as drug entities by the FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or synthetic variations using their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from 1946 to 1980, of the 75 small molecules, 40, or 53.3%, are N or ND. In the 1981 to date time frame the equivalent figures for the N* compounds of the 185 small molecules are 62, or 33.5%, though to these can be added the 58 S* and S*/NMs, bringing the figure to 64.9%. In other areas, the influence of natural product structures is quite marked with, as expected from prior information, the anti-infective area being dependent on natural products and their structures, though as can be seen in the review there are still disease areas (shown in Table 2) for which there are no drugs derived from natural products. Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are still able to identify only two de novo combinatorial compounds (one of which is a little speculative) approved as drugs in this 39-year time frame, though there is also one drug that was developed using the "fragment-binding methodology" and approved in 2012. We have also added a discussion of candidate drug entities currently in clinical trials as "warheads" and some very interesting preliminary reports on sources of novel antibiotics from Nature due to the absolute requirement for new agents to combat plasmid-borne resistance genes now in the general populace. We continue to draw the attention of readers to the recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated"; thus we consider that this area of natural product research should be expanded significantly.
2,560 citations
TL;DR: This review provides an overview of existing CRC-targeted agents and their underlying mechanisms, as well as a discussion of their limitations and future trends.
Abstract: Colorectal cancer (CRC) is among the most lethal and prevalent malignancies in the world and was responsible for nearly 881,000 cancer-related deaths in 2018. Surgery and chemotherapy have long been the first choices for cancer patients. However, the prognosis of CRC has never been satisfying, especially for patients with metastatic lesions. Targeted therapy is a new optional approach that has successfully prolonged overall survival for CRC patients. Following successes with the anti-EGFR (epidermal growth factor receptor) agent cetuximab and the anti-angiogenesis agent bevacizumab, new agents blocking different critical pathways as well as immune checkpoints are emerging at an unprecedented rate. Guidelines worldwide are currently updating the recommended targeted drugs on the basis of the increasing number of high-quality clinical trials. This review provides an overview of existing CRC-targeted agents and their underlying mechanisms, as well as a discussion of their limitations and future trends.
690 citations
TL;DR: Important milestones in the development of the PROTAC technology are addressed, as well as key findings from this previous year are emphasized and future directions of this promising drug discovery modality are highlighted.
389 citations
TL;DR: It is suggested that stringent genetic validation of the mechanism of action of cancer drugs in the preclinical setting may decrease the number of therapies tested in human patients that fail to provide any clinical benefit.
Abstract: Ninety-seven percent of drug-indication pairs that are tested in clinical trials in oncology never advance to receive U.S. Food and Drug Administration approval. While lack of efficacy and dose-limiting toxicities are the most common causes of trial failure, the reason(s) why so many new drugs encounter these problems is not well understood. Using CRISPR-Cas9 mutagenesis, we investigated a set of cancer drugs and drug targets in various stages of clinical testing. We show that-contrary to previous reports obtained predominantly with RNA interference and small-molecule inhibitors-the proteins ostensibly targeted by these drugs are nonessential for cancer cell proliferation. Moreover, the efficacy of each drug that we tested was unaffected by the loss of its putative target, indicating that these compounds kill cells via off-target effects. By applying a genetic target-deconvolution strategy, we found that the mischaracterized anticancer agent OTS964 is actually a potent inhibitor of the cyclin-dependent kinase CDK11 and that multiple cancer types are addicted to CDK11 expression. We suggest that stringent genetic validation of the mechanism of action of cancer drugs in the preclinical setting may decrease the number of therapies tested in human patients that fail to provide any clinical benefit.
382 citations
Cites background from "Kinase inhibitors: the road ahead"
...No drugs have previously been reported to target CDK11, and inhibitors that are specific for single CDKs are difficult to discover due to the sequence similarity among these kinases (44)....
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References
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TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
51,099 citations
TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
28,811 citations
TL;DR: The protein kinase complement of the human genome is catalogued using public and proprietary genomic, complementary DNA, and expressed sequence tag sequences to provide a starting point for comprehensive analysis of protein phosphorylation in normal and disease states and a detailed view of the current state of human genome analysis through a focus on one large gene family.
Abstract: We have catalogued the protein kinase complement of the human genome (the "kinome") using public and proprietary genomic, complementary DNA, and expressed sequence tag (EST) sequences. This provides a starting point for comprehensive analysis of protein phosphorylation in normal and disease states, as well as a detailed view of the current state of human genome analysis through a focus on one large gene family. We identify 518 putative protein kinase genes, of which 71 have not previously been reported or described as kinases, and we extend or correct the protein sequences of 56 more kinases. New genes include members of well-studied families as well as previously unidentified families, some of which are conserved in model organisms. Classification and comparison with model organism kinomes identified orthologous groups and highlighted expansions specific to human and other lineages. We also identified 106 protein kinase pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes and revealed that 244 kinases map to disease loci or cancer amplicons.
7,486 citations
TL;DR: Antibody-mediated blockade of PD-L1 induced durable tumor regression and prolonged stabilization of disease in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer.
Abstract: Background Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. Methods In this multicenter phase 1 trial, we administered intravenous anti–PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti–PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. Results As of February 24, 2012, a total of 207 patients — 75 with non–small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer — had received anti–PD-L1 antibody. The media...
6,812 citations
TL;DR: The paradoxical roles of the tumor microenvironment during specific stages of cancer progression and metastasis are discussed, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
Abstract: Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
5,396 citations