The development and clinical application of inhibitors that target the epidermal growth factor receptor (EGFR) provide important insights for new lung cancer therapies, as well as for the broader field of targeted cancer therapies. We review the results of genetic, biochemical and clinical studies focused on somatic mutations of EGFR that are associated with the phenomenon of oncogene addiction, describing 'oncogenic shock' as a mechanistic explanation for the apoptosis that follows the acute treatment of susceptible cells with kinase inhibitors. Understanding the genetic heterogeneity of epithelial tumours and devising strategies to circumvent their rapid acquisition of resistance to targeted kinase inhibitors are essential to the successful use of targeted therapies in common epithelial cancers.

Epidermal growth factor receptor mutations in lung cancer

The concept of isosterism between relatively simple chemical entities was originally contemplated by James Moir in 1909, a notion further refined by H. G. Grimm’s hydride displacement law and captured more effectively in the ideas advanced by Irving Langmuir based on experimental observations. Langmuir coined the term “isostere” and, 18 years in advance of its actual isolation and characterization, predicted that the physical properties of the then unknown ketene would resemble those of diazomethane. The emergence of bioisosteres as structurally distinct compounds recognized similarly by biological systems has its origins in a series of studies published byHans Erlenmeyer in the 1930s, who extended earlier work conducted by Karl Landsteiner. Erlenmeyer showed that antibodies were unable to discriminate between phenyl and thienyl rings or O, NH, and CH2 in the context of artificial antigens derived by reacting diazonium ions with proteins, a process that derivatized the ortho position of tyrosine, as summarized in Figure 1 The term “bioisostere” was introduced by Harris Friedman in 1950 who defined it as compounds eliciting a similar biological effect while recognizing that compounds may be isosteric but not necessarily bioisosteric. This notion anticipates that the application of bioisosterism will depend on context, relying much less on physicochemical properties as the underlying principle for biochemical mimicry. Bioisosteres are typically less than exact structural mimetics and are often more alike in biological rather than physical properties. Thus, an effective bioisostere for one biochemical application may not translate to another setting, necessitating the careful selection and tailoring of an isostere for a specific circumstance. Consequently, the design of bioisosteres frequently introduces structural changes that can be beneficial or deleterious depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates. The established utility of bioisosteres is broad in nature, extending to improving potency, enhancing selectivity, altering physical properties, reducing or redirecting metabolism, eliminating or modifying toxicophores, and acquiring novel intellectual property. In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compound optimization and the long-term success of drug candidates. Interesting concepts that may have been poorly effective in the context examined are captured, since the ideas may have merit in alternative circumstances. A comprehensive cataloging of bioisosteres is beyond the scope of what will be provided, although a synopsis of relevant isosteres of a particular functionality is summarized in a succinct fashion in several sections. Isosterism has also found productive application in the design and optimization of organocatalysts, and there are several examples in which functional mimicry established initially in a medicinal chemistry setting has been adopted by this community.

Synopsis of some recent tactical application of bioisosteres in drug design.

Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas Yu Zhou,† Jiang Wang,† Zhanni Gu,† Shuni Wang,† Wei Zhu,† Jose ́ Luis Aceña,*,‡,§ Vadim A. Soloshonok,*,‡,∥ Kunisuke Izawa,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastiań, Spain Department of Organic Chemistry, Autońoma University of Madrid, Cantoblanco, 28049 Madrid, Spain IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, 48013 Bilbao, Spain Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, Japan 533-0024

Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II–III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas

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.

The resurgence of covalent drugs

https://www.jbc.org/content/277/48/46265.full.pdf

Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor.

A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.

Synthesis and Structure−Activity Relationships of 6,7-Disubstituted 4-Anilinoquinoline-3-carbonitriles. The Design of an Orally Active, Irreversible Inhibitor of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor-2 (HER-2)

A series of new 6-substituted-4-(3-bromophenylamino)quinazoline derivatives that may function as irreversible inhibitors of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases have been prepared. These inhibitors have, at the C-6 position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(3-bromophenylamino)quinazoline with unsaturated acid chlorides or mixed anhydrides. We show that attaching a basic functional group onto the Michael acceptor results in greater reactivity, due to intramolecular catalysis of the Michael addition and/or an inductive effect of the protonated basic group. This, along with improved water solubility, results in compounds with enhanced biological properties. We present molecular modeling and experimental evidence that these inhibitors interact covalently with the target enzymes. One compound, 16a, was shown to have excellent oral activity in a human epidermoid carcinoma (A431) xenograft model in nude mice.

6-Substituted-4-(3-bromophenylamino)quinazolines as putative irreversible inhibitors of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases with enhanced antitumor activity.

The synthesis and SAR of a series of 4-anilino-6, 7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor (EGF-R) kinase are described. Condensation of 3, 4-dialkoxyanilines with ethyl (ethoxymethylene)cyanoacetate followed by thermal cyclization gave, regiospecifically, 6,7-dialkoxy-4-oxo-1, 4-dihydroquinoline-3-carbonitriles. Chlorination (POCl(3)) followed by the reaction with substituted anilines furnished the 4-anilino-6, 7-dialkoxyquinoline-3-carbonitrile inhibitors of EGF-R kinase. An alternate synthesis of these compounds starts with a methyl 3, 4-dialkoxybenzoate. Nitration followed by reduction (Fe, NH(4)Cl, MeOH-H(2)O) gave a methyl 2-amino-4,5-dialkoxybenzoate. Amidine formation using DMF-acetal followed by cyclization using LiCH(2)CN furnished a 6,7-dialkoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile, which was transformed as before. Compounds containing acid, ester, amide, carbinol, and aldehyde groups at the 3-position of the quinoline ring were also prepared for comparison, as were several 1-anilino-6,7-dimethoxyisoquinoline-4-carbonitriles. The compounds were evaluated for their ability to inhibit the autophosphorylation of the catalytic domain of EGF-R. The SAR of these inhibitors with respect to the nature of the 6,7-alkoxy groups, the aniline substituents, and the substituent at the 3-position was studied. The compounds were further evaluated for their ability to inhibit the growth of cell lines that overexpress EGF-R or HER-2. It was found that 4-anilinoquinoline-3-carbonitriles are effective inhibitors of EGF-R kinase with activity comparable to the 4-anilinoquinazoline-based inhibitors. A new homology model of EGF-R kinase was constructed based on the X-ray structures of Hck and FGF receptor-1 kinase. The model suggests that with the quinazoline-based inhibitors, the N3 atom is hydrogen-bonded to a water molecule which, in turn, interacts with Thr 830. It is proposed that the quinoline-3-carbonitriles bind in a similar manner where the water molecule is displaced by the cyano group which interacts with the same Thr residue.

4-Anilino-6,7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor kinase and their bioisosteric relationship to the 4-anilino-6,7-dialkoxyquinazoline inhibitors.

Brian C. Gruber

Papers

Synthesis and Structure−Activity Relationships of 6,7-Disubstituted 4-Anilinoquinoline-3-carbonitriles. The Design of an Orally Active, Irreversible Inhibitor of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor-2 (HER-2)

6-Substituted-4-(3-bromophenylamino)quinazolines as putative irreversible inhibitors of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases with enhanced antitumor activity.

4-Anilino-6,7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor kinase and their bioisosteric relationship to the 4-anilino-6,7-dialkoxyquinazoline inhibitors.