Peptoids, oligomers ofN-substituted glycines, are described as a motif for the generation ofchemically diverse libraries of novel molecules. Ramachandran-type plots were calculated and indicate a greater diversity of conformational states available for peptoids than for peptides. The monomers incorporate t-butyl-based side-chain and 9-fluorenylmethoxycarbonyl a-amine protection. The controlled oligomerization of the peptoid monomers was performed manually and robotically with in situ activation by either benzotriazol-lyloxytris(pyrrolidino)phosphonium hexafluorophosphate or bromotris(pyrrolidino)phosphonium hexafluorophosphate. Other steps were identical to peptide synthesis using a-(9-fluorenylmethoxycarbonyl)amino acids. A total of 15 monomers and 10 oligomers (peptoids) are described. Preliminary data are presented on the stability of a representative oligopeptoid to enzymatic hydrolysis. Peptoid versions of peptide ligands of three biological systems (bovine pancreatic a-amylase, hepatitis A virus 3C proteinase, and human immunodeficiency virus transactivator-responsive element RNA) were found with affinities comparable to those of the corresponding peptides. The potential use of libraries of these compounds in receptor-or enzyme-based assays is discussed.Broad screening of compound libraries, of broths grown from soil samples, and of synthetic intermediates has been a fruitful method for discovery of lead compounds in pharmaceutical and agrochemical research (e.g., ref. 1). With the advent of automated chemical methods for solid-phase peptide and nucleotide synthesis, and of molecular biological methods for protein and nucleic acid synthesis, the stage has been set for the generation of new kinds of compound libraries, namely, collections of oligomeric biomolecules (2-14). Such libraries have been used to map epitopes for antibody binding, to discern ribonucleotide sequences with specific binding or catalytic activity, and to provide initial leads in receptor-based assays. Advantages of these oligomeric molecules are an almost limitless diversity as a result of their modular structure, the ease with which they can be synthesized and sequenced, and their inherent biological relevance. On the other hand, the metabolic instability of peptides and nucleotides and their poor absorption characteristics mean that any lead sequence will require extensive modification before in vivo activity can be expected.Many of these problems could be avoided if an alternative, modular system was devised, with a basis set of "unnatural" monomers and a method for their controlled oligomerization. A host of chemically and pharmaceutically interesting subunits or modules would generate a diverse and novel set of heteropolymers. Once an interesting compound has been identified from a library of such nonpeptide polymers, it can serve as a lead for drug discovery, further along the road to a metabolically stable drug. Optimized analogs of a lead compound could then be developed rapidly due to the modular synthetic nature of th...

Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.

The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to SARS CoV-1 that caused severe acute respiratory syndrome (SARS) in 2002. Both SARS coronavirus genomes encode two overlapping large polyproteins which are cleaved at specific sites by a cysteine 3C-like protease (3CL pro) in a post-translational processing step that is critical for coronavirus replication. The 3CL pro sequences for CoV-1 and CoV-2 viruses are 100% identical in the catalytic domain that carries out protein cleavage. A research effort that focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CL pro employing ligand-protease structures solved by X-ray crystallography led to the identification of 3 and 4. Preclinical experiments reveal 4 (PF-00835231) as a potent inhibitor of CoV-2 3CL pro with suitable pharmaceutical properties to warrant further development as an intravenous treatment for COVID-19. (~450 kDa) and pp1ab (~750 kDa) that contain overlapping sequences and include a 3C-like cysteine protease (3CL pro). The function of this internally encoded 3CL pro is integral to the processing of these proteins and critical for viral replication. 7 The SARS CoV-1 3CL pro shares a high degree of structural homology and similar substrate specificity with the coronavirus 3C-like cysteine proteases of hCoV-229E and TGEV 8 , but is most similar to the SARS CoV-2 3CL pro. Specifically, the SARS CoV-1 and SARS CoV-2 share 96% identity between their respective 3CL pro sequences and 100% identity in the active site. 8 There are numerous reports of reversible cysteine protease inhibitors which include aldehydes 9-12 , thio-or oxymethylketones 13 , cyclic ketones 14 , amidomethylketones 15 , nitriles 16,17 or various 12-283,039 ± 22,586 13 Me 220 ± 0.5 14 cyc-propyl 182 ± 6 15 tert-butyl 230 ± 5 16 Ph 86 ± 3 17 4-OMe-Ph 79 ± 3 18 4-Me-Ph 87 ± 2 19 4-CN-Ph 53 ± 1 20 4-F-Ph 82 ± 3 21 4-Cl-Ph 97 ± 3 22 2,6-(Cl)2-Ph 62,993 ± 2,501 23 2,6-(F)2-Ph 12,776 ± 594 24 2-OH-4-Cl-Ph 11,525 ± 40 25 2-F, 4-CN-Ph 13,321 ± 2,309 26 2,6-(Me)2-Ph 74 ± 4 27 2,6-(MeO)2-Ph 205 ± 2 28 2-CN-Ph 17 ± 2 a See Experimental Section for details on assay methods, values were calculated from at least eight data points with at least two independent determinations.

Purpose: Axitinib (AG-013736) is a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases 1to 3 that is in clinical development for the treatment of solid tumors. We provide a comprehensive description of its in vitro characteristics and activities, in vivo antiangiogenesis, and antitumor efficacy and translational pharmacology data. Experimental Design: The potency, kinase selectivity, pharmacologic activity, and antitumor efficacy of axitinib were assessed in various nonclinical models. Results: Axitinib inhibits cellular autophosphorylation of VEGF receptors (VEGFR) with picomolar IC 50 values. Counterscreening across multiple kinase and protein panels shows it is selective for VEGFRs. Axitinib blocks VEGF-mediated endothelial cell survival, tube formation, and downstream signaling through endothelial nitric oxide synthase, Akt and extracellular signal-regulated kinase. Following twice daily oral administration, axitinib produces consistent and dose-dependent antitumor efficacy that is associated with blocking VEGFR-2 phosphorylation, vascular permeability, angiogenesis, and concomitant induction of tumor cell apoptosis. Axitinib in combination with chemotherapeutic or targeted agents enhances antitumor efficacy in many tumor models compared with single agent alone. Dose scheduling studies in a human pancreatic tumor xenograft model show that simultaneous administration of axitinib and gemcitabine without prolonged dose interruption or truncation of axitinib produces the greatest antitumor efficacy. The efficacious drug concentrations predicted in nonclinical studies are consistent with the range achieved in the clinic. Although axitinib inhibits platelet-derived growth factor receptors and KIT with nanomolar in vitro potencies, based on pharmacokinetic/pharmacodynamic analysis, axitinib acts primarily as a VEGFR tyrosine kinase inhibitor at the current clinical exposure. Conclusions: The selectivity, potency for VEGFRs, and robust nonclinical activity may afford broad opportunities for axitinib to improve cancer therapy.

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.