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Journal ArticleDOI: 10.1080/17460441.2021.1832079

Approaches to mitigate the risk of serious adverse reactions in covalent drug design

04 Mar 2021-Expert Opinion on Drug Discovery (Taylor & Francis)-Vol. 16, Iss: 3, pp 275-287
Abstract: Covalent inhibition of target proteins using high affinity ligands bearing weakly electrophilic warheads is being adopted increasingly as design strategy in the discovery of novel therapeutics, and...

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6 results found

Journal ArticleDOI: 10.1016/J.PHRS.2021.105422
Abstract: Because dysregulation of protein kinases owing to mutations or overexpression plays causal roles in human diseases, this family of enzymes has become one of the most important drug targets of the 21st century. Of the 62 protein kinases inhibitors that are approved by the FDA, seven of them form irreversible covalent adducts with their target enzymes. The clinical success of ibrutinib, an inhibitor of Bruton tyrosine kinase, in the treatment of mantle cell lymphomas following its approval in 2013 helped to overcome a general bias against the development of irreversible drug inhibitors. The other approved covalent drugs include acalabrutinib and zanubrutinib, which also inhibit Bruton tyrosine kinase. Furthermore afatinib, dacomitinib, and osimertinib, inhibitors of members of the epidermal growth factor receptor family (ErbB1/2/3/4), are used in the treatment of non-small cell lung cancers. Neratinib is an inhibitor of ErbB2 and is used in the treatment of ErbB2/HER2-positive breast cancer. The seven drugs considered in this review have a common mechanism of action; this process involves the addition of a protein cysteine thiolate anion (protein‒S:-) to an acrylamide derivative (CH2=CHC(=O)N(H)R) where R represents the pharmacophore. Such reactions are commonly referred to as Michael additions and each reaction results in the formation of a covalent bond between carbon and sulfur; the final product is a thioether. This process consists of two discrete steps; the first step involves the reversible association of the drug with its target enzyme so that a weakly electrophilic functionality, a warhead, is bound near an appropriately positioned nucleophilic cysteine. In the second step, a reaction occurs between the warhead and the target enzyme cysteine to form a covalently modified and inactive protein. For this process to work, the warhead must be appropriately juxtaposed in relationship to the cysteinyl thiolate so that the covalent addition can occur. Covalent inhibitors have emerged from the ranks of drugs to be avoided to become an emerging paradigm. Much of this recent success can be attributed to the clinical efficacy of ibrutinib as well as the other antagonists covered in this review. Moreover, the covalent inhibitor methodology is swiftly gaining acceptance as a valuable component of the medicinal chemist's toolbox and is primed to make a significant impact on the development of enzyme antagonists and receptor modulators.

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Topics: Ibrutinib (57%), Bruton's tyrosine kinase (53%), Neratinib (53%) ... read more

8 Citations

Open accessJournal ArticleDOI: 10.1073/PNAS.2013691118
Abstract: Despite their desirable attributes, boronic acids have had a minimal impact in biological contexts. A significant problem has been their oxidative instability. At physiological pH, phenylboronic acid and its boronate esters are oxidized by reactive oxygen species at rates comparable to those of thiols. After considering the mechanism and kinetics of the oxidation reaction, we reasoned that diminishing electron density on boron could enhance oxidative stability. We found that a boralactone, in which a carboxyl group serves as an intramolecular ligand for the boron, increases stability by 104-fold. Computational analyses revealed that the resistance to oxidation arises from diminished stabilization of the p orbital of boron that develops in the rate-limiting transition state of the oxidation reaction. Like simple boronic acids and boronate esters, a boralactone binds covalently and reversibly to 1,2-diols such as those in saccharides. The kinetic stability of its complexes is, however, at least 20-fold greater. A boralactone also binds covalently to a serine side chain in a protein. These attributes confer unprecedented utility upon boralactones in the realms of chemical biology and medicinal chemistry.

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Topics: Boronic acid (61%), Phenylboronic acid (57%)

7 Citations

Open accessJournal ArticleDOI: 10.3390/IJMS21239269
Abstract: The nonreceptor tyrosine TEC kinases are key regulators of the immune system and play a crucial role in the pathogenesis of diverse hematological malignancies. In contrast to the substantial efforts in inhibitor development for Bruton's tyrosine kinase (BTK), specific inhibitors of the other TEC kinases, including the bone marrow tyrosine kinase on chromosome X (BMX), remain sparse. Here we present a novel class of dual BMX/BTK inhibitors, which were designed from irreversible inhibitors of Janus kinase (JAK) 3 targeting a cysteine located within the solvent-exposed front region of the ATP binding pocket. Structure-guided design exploiting the differences in the gatekeeper residues enabled the achievement of high selectivity over JAK3 and certain other kinases harboring a sterically demanding residue at this position. The most active compounds inhibited BMX and BTK with apparent IC50 values in the single digit nanomolar range or below showing moderate selectivity within the TEC family and potent cellular target engagement. These compounds represent an important first step towards selective chemical probes for the protein kinase BMX.

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Topics: Bruton's tyrosine kinase (65%), Tyrosine kinase (58%), Janus kinase (57%) ... read more

2 Citations

Journal ArticleDOI: 10.1016/J.TAAP.2021.115578
Jonathan Werner1, Rhian Davies1, Jan Wahlstrom1, Upendra P. Dahal1  +9 moreInstitutions (1)
Abstract: Sotorasib is a first-in class KRASG12C covalent inhibitor in clinical development for the treatment of tumors with the KRAS p.G12C mutation. In the nonclinical toxicology studies of sotorasib, the kidney was identified as a target organ of toxicity in the rat but not the dog. Renal toxicity was characterized by degeneration and necrosis of the proximal tubular epithelium localized to the outer stripe of the outer medulla (OSOM), which suggested that renal metabolism was involved. Here, we describe an in vivo mechanistic rat study designed to investigate the time course of the renal toxicity and sotorasib metabolites. Renal toxicity was dose- and time-dependent, restricted to the OSOM, and the morphologic features progressed from vacuolation and necrosis to regeneration of tubular epithelium. The renal toxicity correlated with increases in renal biomarkers of tubular injury. Using mass spectrometry and matrix-assisted laser desorption/ionization, a strong temporal and spatial association between renal toxicity and mercapturate pathway metabolites was observed. The rat is reported to be particularly susceptible to the formation of nephrotoxic metabolites via this pathway. Taken together, the data presented here and the literature support the hypothesis that sotorasib-related renal toxicity is mediated by a toxic metabolite derived from the mercapturate and β-lyase pathway. Our understanding of the etiology of the rat specific renal toxicity informs the translational risk assessment for patients.

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Topics: Kidney (60%), Nephrotoxicity (57%), Toxicity (57%) ... read more

2 Citations


88 results found

Open accessJournal ArticleDOI: 10.1038/NATURE12796
Jonathan M. Ostrem1, Ulf Peters1, Martin L. Sos1, James A. Wells1  +1 moreInstitutions (1)
28 Nov 2013-Nature
Abstract: Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies. Efforts to target this oncogene directly have faced difficulties owing to its picomolar affinity for GTP/GDP and the absence of known allosteric regulatory sites. Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent on relative nucleotide affinity and concentration. This gives GTP an advantage over GDP and increases the proportion of active GTP-bound Ras. Here we report the development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras(G12C). These compounds rely on the mutant cysteine for binding and therefore do not affect the wild-type protein. Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. Binding of these inhibitors to K-Ras(G12C) disrupts both switch-I and switch-II, subverting the native nucleotide preference to favour GDP over GTP and impairing binding to Raf. Our data provide structure-based validation of a new allosteric regulatory site on Ras that is targetable in a mutant-specific manner.

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Topics: GTPase (59%), GTP' (59%), Small GTPase (58%) ... read more

1,153 Citations

Journal ArticleDOI: 10.1038/NRD3410
Abstract: Covalent drugs have proved to be successful therapies for various indications, but largely owing to safety concerns, they are rarely considered when initiating a target-directed drug discovery project. There is a need to reassess this important class of drugs, and to reconcile the discordance between the historic success of covalent drugs and the reluctance of most drug discovery teams to include them in their armamentarium. This review surveys the prevalence and pharmacological advantages of covalent drugs, discusses how potential risks and challenges may be addressed through innovative design, and presents the broad opportunities provided by targeted covalent inhibitors.

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1,140 Citations

Open accessJournal ArticleDOI: 10.1056/NEJMOA1400029
Abstract: Background Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance. Methods We performed whole-exome sequencing at baseline and the time of relapse on samples from six patients with acquired resistance to ibrutinib therapy. We then performed functional analysis of identified mutations. In addition, we performed Ion Torrent sequencing for identified resistance mutations on samples from nine patients with prolonged lymphocytosis. Results We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutati...

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Topics: Ibrutinib (70%), Acalabrutinib (68%), Bruton's tyrosine kinase (63%) ... read more

845 Citations

Journal ArticleDOI: 10.1021/TX034170B
Abstract: It is generally accepted that there is neither a well-defined nor a consistent link between the formation of drug-protein adducts and organ toxicity. Because the potential does exist, however, for these processes to be causally related, the general strategy at Merck Research Laboratories has been to minimize reactive metabolite formation to the extent possible by appropriate structural modification during the lead optimization stage. This requires a flexible approach to defining bioactivation issues in a variety of metabolism vectors and typically involves the initial use of small molecule trapping agents to define the potential for bioactivation. At some point, however, there is a requirement to synthesize a radiolabeled tracer and to undertake covalent binding studies in vitro, usually in liver microsomal (and sometimes hepatocyte) preparations from preclinical species and human, and also in vivo, typically in the rat. This paper serves to provide one pragmatic approach to addressing the issue of bioactivation from an industry viewpoint based on protocols adopted by Merck Research Laboratories. The availability of a dedicated Labeled Compound Synthesis group, coupled to a close working relationship between Drug Metabolism and Medicinal Chemistry, represents a framework within which this perspective becomes viable; the overall aim is to bring safer drugs to patients.

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654 Citations

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