Cyclopropyl as a versatile tool in the development of kinase-targeted therapeutics.

La question a ete abordee de facon chronologique et selon la problematique suivante : quel fut le role de l'Etat dans la definition de la nation au XIXeme siecle ? Des l'epoque coloniale, l'unification territoriale, linguistique et religieuse, le metissage et l'âprete de la lutte contre les araucans ont cree une cohesion parmi les habitants de la zone centrale du Chili. Le mouvement d'emancipation, de caractere aristocratique, fut neanmoins accompagne de mesures visant a integrer les differents groupes sociaux et ethniques a la nation creole et les dirigeants favoriserent la naissance d'une culture nationale. L'independance ne devait pas se limiter a une perception politique, il s'agissait aussi de creer une nouvelle identite culturelle basee sur l'exaltation du patriotisme. L'Etat definit tres tot la nation en termes culturels et affectifs et non pas ethniques. Le droit du sol fut immediatement reconnu par les constitutions. C'est autour d'un projet, celui du progres et de la modernite que s'est cimentee la nation chilienne. Apres l'independance, le Chili connut plusieurs guerres, contre la Bolivie et le Perou de Santa Cruz en 1836, contre l’Espagne en 1864 et enfin la guerre du Pacifique qui eut le plus gros impact sur l'ensemble de la population car elle fit naitre une cohesion inedite face a la menace exterieure. Ainsi, le Chili a construit son identite dans un premier temps en rejetant l’Espagne et dans un second temps en se demarquant culturellement et politiquement des pays voisins. La fierte nationale nee de la reussite economique, culturelle et militaire sera une des composantes essentielles de l'emergence d'une conscience nationale au Chili a la fin du XIXeme siecle.

Pyrazolo[1,5-a]pyrimidine scaffold-based small molecules: From bench to FDA-approved TRK kinase inhibitors (Part 1).

Emerging drug discovery ecosystems.

Many human malignancies are associated with aberrant regulation of protein or lipid kinases due to mutations, chromosomal rearrangements and/or gene amplification. Protein and lipid kinases represent an important target class for treating human disorders. This review focus on 'the 10 things you should know about protein kinases and their inhibitors', including a short introduction on the history of protein kinases and their inhibitors and ending with a perspective on kinase drug discovery. Although the '10 things' have been, to a certain extent, chosen arbitrarily, they cover in a comprehensive way the past and present efforts in kinase drug discovery and summarize the status quo of the current kinase inhibitors as well as knowledge about kinase structure and binding modes. Besides describing the potentials of protein kinase inhibitors as drugs, this review also focus on their limitations, particularly on how to circumvent emerging resistance against kinase inhibitors in oncological indications.

Rule of five violations among the FDA-approved small molecule protein kinase inhibitors

La chimie crée son objet. Cette faculté créatrice, semblable à celle de l’art lui-même, la distingue essentiellement des sciences naturelles et historiques. Marcelin Berthelot, La Synthèse chimique, Alcan, Paris, 1887 This famous quote from Marcelin Berthelot (its English translation is “Chemistry creates its object. This creative faculty, similar to that of art itself, distinguishes it essentially from natural and historical sciences.”) exemplifies like no other the ability of the chemist to create new molecules with novel structures and, following therefrom, novel properties. Because of this creative power, chemistry, and in particular synthetic chemistry, has been assigned multiple enabling roles and several of its sister disciplines have grown “chemical” branches such as “chemical physics”.1 Among these disciplines, “chemical biology” is a younger cousin. While the name was coined at least four decades ago,1 the current understanding of the term was shaped only within the last two decades. The field evolved from bioorganic chemistry, biochemistry, cell biology, and pharmacology, but synthetic organic chemists played a leading role in its inauguration. For instance, Stuart L. Schreiber and K. C. Nicolaou served as Editors of the journal Chemistry & Biology, “the first journal dedicated to the expanding intellectual area in which chemical approaches and biological disciplines overlap.” As they stress in their inaugural Editorial in the first issue: “Both of us started professional life as strict organic chemists, with little knowledge of biology and not much expectation that we would ever need to know any.” [2] Since then, the development and application of organic synthesis methodology to achieve a greater understanding of biology at the molecular level has emerged as one major area of research in chemical biology. For instance, labeling of biomolecules has greatly advanced in the last decades, based largely on the development of novel biomacromolecule synthesis and ligation techniques, which are often rooted in classical organic synthesis methods such as the Huisgen 1,3-dipolar cycloaddition and the Staudinger reaction. Among the various applications of organic synthesis methodology in chemical biology research, it is most likely that the use of small-molecule probes as tools for unraveling and manipulating the inner workings of the cell (chemical genetics) today is commonly associated with the term “chemical biology”. While major studies and efforts have been made during the last decades to fill the chemical toolbox required to meet this daunting task and to equip the chemical biologist with the right “tools” in the struggle to decipher the secrets of nature, this endeavor has only just begun. Notably, although large compound libraries are commercially available these days, their structural complexity and diversity remain fairly limited, and in high-content assays, their performance often leaves room for substantial improvement. Higher structural complexity and incorporation of stereogenic centers often positively correlate with bioactivity, thus calling for the synthesis and application of complex compound classes in chemical biology research that expand the currently accessible tool and probe candidates to novel scaffold classes. This demand can only be met by the continuous introduction of novel synthesis methodology and the development of creative solutions to the problem of making increasingly complex compounds available with higher efficiency and practicability in the formats of compound-collection synthesis. Therefore, the synthesis of structurally and stereochemically complex molecular architectures is at the heart of chemical biology research. Chemical biology needs continuous input from organic synthesis, and organic synthesis may find challenging and unprecedented synthesis targets with an immediate application in the problems faced by chemical biologists: chemical biology and organic synthesis are brothers-in-arms! Ideally, to lend the brotherhood strength and to develop it to maximum impact, both chemical and biological expertise should be established under one roof, that is, within a given research group. As ideal as it would be, such an interdisciplinary team is hard to establish. Limitations arise on one hand from the different cultures of the two sciences and the core expertise of the leading scientists, who usually were trained and started their career in either chemistry or biology. On the other hand, establishing and operating a full chemistry and biology infrastructure is very cost-intensive, and funds on the required scale often are simply not available. Hence, only few groups worldwide can fulfill these requirements. Alternatively, collaboration between different research groups is necessary in chemical biology research, and, indeed, many of the best results obtained in this science represent multiteam efforts. If productive collaborations with mutual appreciation of the partners and their scientific contribution can be established, from a scientific point of view, this brotherhood may actually be the better approach to tackle demanding scientific problems. The combined expertise of the partners in chemistry and biology usually will allow deeper insights to be obtained and high-quality research in both sciences to be performed. This brotherhood may prove vital to yet another sector of science in the near future, that is, to drug discovery. Chemical biology is partly rooted in cell biology and pharmacology, and its repertoire of methods extents into small-molecule synthesis, determination of bioactivity, and identification and validation of small molecule cellular targets. If the small molecules employed in chemical biology research have druglike properties, and modulation of the activity of their cellular targets can be tied to a disease-modifying effect, the link to drug discovery is obvious. In fact, fully fledged chemical biology research programs have the potential to simultaneously produce novel insights into fundamental biological mechanisms, deliver new targets, and supply small-molecule modulators of target activity. Therefore, major challenges in drug discovery may inspire chemical biology research and by extension, organic synthesis endeavors. Conversely, the outcomes of a chemical biology investigation may fuel efforts in drug discovery. This alliance may prove instrumental as a key driver for future research in the pharmaceutical industry. Facing major challenges, pharmaceutical companies very recently have increased collaboration with academic institutions far beyond the occasional support of individual smaller projects (see, for example, reference 3). In so doing, the industry may be well advised to listen to its own opinion leaders. In June 2011, Mark Bunnage (Pfizer) wrote: “This change in model reflects the reality that the vast majority of the initial breakthroughs in target biology research occurs in the academic research environment. It is thus considered essential for pharmaceutical companies and their scientists to become better connected with the external research environment and develop a more extended network of partnerships and genuine collaborations with academia. …︁ It is thus essential for medicinal chemists in industry to increase their awareness of chemical biology approaches and build these into their armamentarium to enable drug discovery.” [4]—He is right! A successful and seminal example of such a fruitful collaboration between academia and industry is the Chemical Genomics Centre (CGC) of the Max Planck Society (Max-Planck Gesellschaft, MPG). The CGC was established in 2005 as a joint initiative of the MPG, Merck KGaA, Schering AG, Bayer CropScience AG, and Organon B.V. Research in the CGC is focused on challenging unsolved problems in chemistry and biology of major relevance to drug discovery, such as stabilization of protein–protein interactions by small molecules and the development of allosteric kinase inhibitors. Both the companies and the MPG funded independent research groups that developed the basic science and transferred it to the companies. If appointment of the group leaders to professorships and integration of the developed technologies into the internal project pipelines of the companies are accepted as stringent criteria for measuring success from both the academic and the industrial point of view, then the establishment of the CGC was a major success. Accordingly, after the first funding period of the CGC (2005–2010) the MPG and Merck KGaA, AstraZeneca AB, Boehringer Ingelheim Pharma GmbH & Co. KG, Bayer Pharma AG, and Bayer CropScience AG have established “CGC II”, and the first research group leaders have been appointed very recently. The success of the CGC and related initiatives suggests that it may be more than advisable to those engaged in drug discovery to take the final verses of Schiller’s poem “The Hostage” to heart (translation by Scott Horton):5 He gazed upon them long in amazement, And then spoke: “You have succeeded, You have turned my heart, In truth, fidelity is no idle delusion, So accept me also as your friend, I would be—grant me this request— The third in your band!”

Drug resistance remains one of the biggest challenges in kinase inhibitor therapy, particularly in cancers where prolonged treatment fosters the emergence of resistant mutations. These mutations often alter amino acid residues within the kinase active site, reshaping the local chemical environment and disrupting critical drug-target interactions. The resulting changes - such as steric hindrance, loss of key hydrogen bonds, elimination of reactive residues, or other structural incompatibilities - can drastically reduce drug efficacy. To counter these effects, drug molecules must undergo tailored chemical adaptation - strategic modifications that align their molecular features (e.g., geometric shape, stereochemistry, acidity/basicity, and reactivity) with the mutation-altered changes in steric, electronic, and reactivity landscapes within the mutant kinase binding pocket. In this Account, we describe how the principles of chemical adaptation guided our rational design of small molecule kinase inhibitors to overcome clinically relevant resistance. Over the past 18 years, these efforts have culminated in the discovery and approval of two targeted therapies - olverembatinib and limertinib - as well as the advancement of several clinical-stage candidates.Olverembatinib was developed to treat chronic myeloid leukemia patients harboring the gatekeeper Bcr-AblT315I mutation, which confers resistance to first- and second-generation inhibitors. To mitigate steric clashes and restore lost hydrogen bonding, we introduced an alkyne linker to accommodate conformational shifts, and a 1H-pyrazolo[3,4-b]pyridinyl moiety to form new stabilizing hydrogen bonds within the hinge region. For non-small cell lung cancer patients with EGFRT790M-driven resistance, we designed heterocyclic scaffolds bearing electrophilic groups capable of covalently targeting Cys797, enabling high selectivity for EGFR mutants while sparing wild-type EGFR. This approach led to the development of limertinib, a potent and mutant-selective third-generation EGFR inhibitor approved for treating patients with or without EGFRT790M mutations, including those with brain metastases. Building on this success, we are advancing next-generation inhibitors designed to overcome additional resistance mutations such as EGFRL858R/T790M/C797S.In summary, this Account highlights the medicinal chemistry strategies underlying the approvals of olverembatinib and limertinib, illustrating how chemical adaptation can be harnessed to overcome kinase inhibitor resistance. Moving forward, we aim to expand this concept across broader drug modalities and therapeutic targets to address ongoing clinical challenges.

A Protein kinase targeted.A number of these molecules are broad-spectrum kinase inhibitors.B Staurosporine class represents examples of broad-spectrum kinase inhibitors.PCD, preclinical development.These compounds may have progressed to phase I clinical trials.

This review article illustrates the growing use of azaindole derivatives as kinase inhibitors and their contribution to drug discovery and innovation. The different protein kinases which have served as targets and the known molecules which have emerged from medicinal chemistry and Fragment-Based Drug Discovery (FBDD) programs are presented. The various synthetic routes used to access these compounds and the chemical pathways leading to their synthesis are also discussed. An analysis of their mode of binding based on X-ray crystallography data gives structural insights for the design of more potent and selective inhibitors.

Fluorescence imaging is a powerful tool that permits visualization of specific cell states within a population; however, existing methods for fluorescence labeling cannot be easily applied in many biological systems. Unlike antibodies, small molecule proteins can be cell permeable and therefore useful in live-cell and in vivo imaging experiments; moreover, small molecule probes do not require genetic manipulation of cells. Protein kinases are in many ways ideal targets for the development of selective fluorescent small molecule probes. This is because protein kinases are involved in most cellular processes and changes in their localization, accessibility, and abundance are associated with changes in cellular state. In addition, drug discovery and chemical biology efforts have in recent decades produced many selective, cell permeable small molecule ligands of specific cellular kinases. Here we describe our attempts to leverage existing, well-characterized kinase inhibitors to develop fluorescent small molecule probes for use as imaging tools in cancer biology. BODIPYconjugated kinase inhibitors, such as Mps1-IN-1 and BI2536 were synthesized. Their inhibition ability and immunofluorescence staining were tested. We demonstrated the utility of BI-BODIPY as a cell permeable probe for monitoring PLK localization. This result serves as the foundation for more sophisticated live-cell and in vivo imaging experiments that we are currently pursuing. This study also provides proof of concept for extension of this strategy to convert other small molecule kinase inhibitors to probes that can analogously be used to monitor localization of their respective kinases. 1. N. Kwiatkowski, N. Jelluma, P. Filippakopoulos, M. Soundararajan, M. S. Manak, M. Kwon, H. G. Choi, T. Sim, Q. L. Deveraux, S. Rottmann, D. Pellman, J. V. Shah, G. J. Kops, S. Knapp and N. S. Gray, Nat. Chem. Biol, 2010, 359. 2. P. Lenart, M. Petronczki, M. Steegmaier, B. Di Fiore, J. J. Lipp, M. Hoffmann, W. J. Rettig, N. Kraut and J. M. Peters, Curr. Biol, 2007, 304. 3. Z. Zhang, N. Kwiatkowski, H. Zeng, S. M. Lim, N. S. Gray, W. Zhang, P. L. Yang, Mol. BioSystems 2012, 8, 2523. N N N N O N H O N H O N N O N N B F F

Protein kinases play a crucial role in cancer initiation, progression, and therapeutic resistance by regulating signalling pathways involved in tumour growth and survival. Consequently, they represent major targets in anticancer drug discovery. Among heterocyclic scaffolds explored in kinase inhibitor design, benzimidazole has emerged as a privileged structure due to its strong hydrogen-bonding capability and structural resemblance to purine moieties. Triazole motifs are also widely incorporated into bioactive molecules because of their metabolic stability, favourable electronic properties, and ability to establish key interactions within kinase active sites. This review aims to summarise and critically discuss benzimidazole- and triazole-based kinase inhibitors, both as individual scaffolds and as hybrid systems, with emphasis on their kinase targets and multitarget potential. The relevant literature was surveyed from major scientific databases focusing on studies describing the synthesis, biological evaluation, and molecular modelling of benzimidazole- and triazole-containing kinase inhibitors. Numerous studies demonstrate that both benzimidazole and triazole scaffolds exhibit significant kinase inhibitory activity against oncogenic targets, including EGFR, cyclin-dependent kinases (CDKs), and components of the PI3K/Akt/mTOR signalling pathway. Hybrid molecules combining these pharmacophores frequently enhance binding interactions and facilitate the development of multitarget kinase inhibitors. Structure-activity relationship trends indicate that pharmacophore accessibility, substitution patterns, and linker architecture influence inhibitory potency and selectivity. Overall, benzimidazole- and triazole-based scaffolds represent promising platforms for developing next-generation multitarget anticancer agents and provide valuable insights for the rational design of improved kinase inhibitors.

Protein kinases are involved in a variety of diseases including cancer, inflammation, and autoimmune disorders. Although the development of new kinase inhibitors is a major focus in pharmaceutical research, a large number of kinases remained so far unexplored in drug discovery projects. The selection and assessment of targets is an essential but challenging area. Today, a few thousands of experimentally determined kinase structures are available, covering about half of the human kinome. This large structural source allows guiding the target selection via structure-based druggability prediction approaches such as DoGSiteScorer. Here, a thorough analysis of the ATP pockets of the entire human kinome in the DFG-in state is presented in order to prioritize novel kinase structures for drug discovery projects. For this, all human kinase X-ray structures available in the PDB were collected, and homology models were generated for the missing part of the kinome. DoGSiteScorer was used to calculate geometrical and physicochemical properties of the ATP pockets and to predict the potential of each kinase to be druggable. The results indicate that about 75% of the kinome are in principle druggable. Top ranking structures comprise kinases that are primary targets of known approved drugs but additionally point to so far less explored kinases. The presented analysis provides new insights into the druggability of ATP binding pockets of the entire kinome. We anticipate this comprehensive druggability assessment of protein kinases to be helpful for the community to prioritize so far untapped kinases for drug discovery efforts.

Protein kinases are central regulators of cell signaling and play pivotal roles in a wide array of diseases, most notably cancer and autoimmune disorders. The clinical success of kinase inhibitors-such as imatinib and osimertinib-has firmly established kinases as valuable drug targets. However, the development of selective, potent inhibitors remains challenging due to the conserved nature of the ATP-binding site, off-target effects, resistance mutations, and patient-specific variability. Recent advances in artificial intelligence (AI) and machine learning (ML) offer transformative solutions to these obstacles across the drug discovery pipeline. This review explores how AI/ML methods, including deep learning, graph neural networks, and generative models, are revolutionizing the design, optimization, and repurposing of kinase inhibitors. We detail applications in target identification, virtual screening, structure-activity relationship modeling, resistance prediction, and clinical trial design. Representative case studies-such as AI-optimized BTK and EGFR inhibitors-highlight real-world impact. We also examine current limitations, including data sparsity, model interpretability, and translational gaps between in silico and experimental results. Finally, we discuss emerging directions such as federated learning, personalized kinase inhibitors, and AI-enabled combination therapies. By integrating computational innovation with medicinal chemistry, AI/ML holds immense promise to accelerate and refine the next generation of kinase-targeted therapeutics.

Precision medicine's quick development has transformed the way cancer is treated, and because small-molecule kinase inhibitors can specifically block the abnormal signaling pathways that cause tumor growth and progression, they are now a key component of targeted therapy. This review explores the most recent advancements in kinase inhibitor design and optimization, with a focus on novel drug scaffolds, improved structure-activity relationships (SARs), and molecular modification techniques meant to improve target selectivity, potency, and pharmacokinetic profiles. Emerging strategies to combat resistance mechanisms are heavily emphasized, such as the use of dual-target inhibitors that block parallel signaling cascades, allosteric modulators that bind to non-ATP sites, and combination therapies that work in concert to increase efficacy while reducing resistance. A thorough summary of the kinase inhibitors that are now FDA-approved for use in treating different forms of cancer is also included in the review, along with information on their safety profiles, clinical effectiveness, and changing indications of usage. Additionally, it examines encouraging results from preclinical research and ongoing clinical studies assessing nextgeneration kinase inhibitors, which have the potential to further customize cancer treatment. In order to improve patient outcomes, address therapeutic resistance, and broaden the therapeutic scope of kinase-targeted interventions in oncology, the review concludes by highlighting future research directions, such as drug repurposing, computational drug discovery, and advanced precision oncology approaches.

Tuberculosis, caused by Mycobacterium tuberculosis, remains one of the leading causes of death worldwide despite extensive research, directly observed therapy using multidrug regimens, and the widespread use of a vaccine. The majority of patients harbor the bacterium in a state of metabolic dormancy. New drugs with novel modes of action are needed to target essential metabolic pathways in M. tuberculosis; ATP-competitive enzyme inhibitors are one such class. Previous screening efforts for ATP-competitive enzyme inhibitors identified several classes of lead compounds that demonstrated potent anti-mycobacterial efficacy as well as tolerable levels of toxicity in cell culture. In this report, a probe-based chemoproteomic approach was used to selectively profile the M. tuberculosis ATP-binding proteome in normally growing and hypoxic M. tuberculosis. From these studies, 122 ATP-binding proteins were identified in either metabolic state, and roughly 60% of these are reported to be essential for survival in vitro. These data are available through ProteomeXchange with identifier PXD000141. Protein families vital to the survival of the tubercle bacillus during hypoxia emerged from our studies. Specifically, along with members of the DosR regulon, several proteins involved in energy metabolism (Icl/Rv0468 and Mdh/Rv1240) and lipid biosynthesis (UmaA/Rv0469, DesA1/Rv0824c, and DesA2/Rv1094) were found to be differentially abundant in hypoxic versus normal growing cultures. These pathways represent a subset of proteins that may be relevant therapeutic targets for development of novel ATP-competitive antibiotics.