VCP (also known as p97 or Cdc48p in yeast) is an AAA(+) ATPase regulating endoplasmic reticulum-associated degradation. After high-throughput screening, we developed compounds that inhibit VCP via different mechanisms, including covalent modification of an active site cysteine and a new allosteric mechanism. Using photoaffinity labeling, structural analysis and mutagenesis, we mapped the binding site of allosteric inhibitors to a region spanning the D1 and D2 domains of adjacent protomers encompassing elements important for nucleotide-state sensing and ATP hydrolysis. These compounds induced an increased affinity for nucleotides. Interference with nucleotide turnover in individual subunits and distortion of interprotomer communication cooperated to impair VCP enzymatic activity. Chemical expansion of this allosteric class identified NMS-873, the most potent and specific VCP inhibitor described to date, which activated the unfolded protein response, interfered with autophagy and induced cancer cell death. The consistent pattern of cancer cell killing by covalent and allosteric inhibitors provided critical validation of VCP as a cancer target.

The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine-threonine and tyrosine kinases, new analogues were synthesized. Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified as a drug candidate for further development. Compound 28 is currently undergoing phase I and phase II clinical trials.

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Valosine-containing protein (VCP), also known as p97 or cdc48 in yeast, is a highly abundant protein belonging to the AAA ATPase family involved in a number of essential cellular functions, including ubiquitin-proteasome mediated protein degradation, Golgi reassembly, transcription activation, and cell cycle control. Altered expression of VCP has been detected in many cancer types sometimes associated with poor prognosis. Furthermore, VCP mutations are causative of some neurodegenerative disorders. In this paper we report the discovery, synthesis, and structure-activity relationships of substituted 2-aminopyrimidines, representing a new class of reversible VCP inhibitors. This class of compounds, identified in a HTS campaign against recombinant VCP, has been progressively expanded and manipulated to increase biochemical potency and gain cellular activity.

The availability of small organic molecules covering as much chemical space as possible is seen as the only means that guarantees potential modulation of the many biological targets that are ultimately being unveiled by genomics. Therefore diversity oriented organic synthesis is rapidly becoming one of the paradigms in the process of modern drug discovery. This has spurred research in those fields of chemical investigation that lead to the rapid assembly of not only molecular diversity, but also molecular complexity. As a consequence multi-component as well as domino or related reactions are witnessing a new spring. Coupling these one-pot processes with solid-phase synthesis offers new perspectives for the preparation of both primary and thematic libraries. The progresses recently made in this field that perfectly suits the needs of modern drug discovery are the subject of the present review.

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In this work we report the synthesis of the 1-oxo-1,2,3,4-tetrahydro-b-carboline scaffold with two regioselectively functionalizable positions, starting from a readily available indole precursor.Many natural products, particularly marine indole alkaloids, contain the b-carboline skeleton, 1 a structure very often associated with interesting biological activity. 2 Recently, molecules with a 1-oxo-1,2,3,4-tetrahydro-b-carboline scaffold have been found to inhibit kinase MAPKAP-K2, 3 to exert an antidepressant action, 4 and showed agonistic activity on mGluR1 receptor. 5The synthesis of this particular system (Scheme 1) has mostly been accomplished through the Fischer indole cyclization of aryl hydrazones 2, 4,6 from the 3-(2-aminoethyl)indole derivative 4 which is converted into the corresponding isocyanato intermediate 3 and then cyclized in situ, 7 and, more recently, through an intramolecular platinum-catalyzed alkylation of indoles with olefins 8. 8The first synthetic approach is mainly employed for the preparation of compounds with different substituents at C6 by using para-substituted aniline precursors 7. In these cases, cyclization of intermediate hydrazone 2 can involve either of the two NH ortho-positions, which affords the same C6 substituted product. Compounds with alkyl substituents at C5-8 have also been obtained by this approach, although methyl substituents have been observed to migrate during the hydrazone cyclization. 6j The isocyanato route has been described, for example, starting from L-tryptophan methyl ester, 7a thus affording the 3-substituted derivative.The palladium-catalyzed intramolecular alkylation allowed the synthesis of a C4 substituted 1-oxo-1,2,3,4-tetrahydro-b-carboline along with a variety of C1, C2, and/ or C4 substituted b-carbolines. 9With the aim of preparing a library of differently substituted 1-oxo-1,2,3,4-tetrahydro-b-carboline derivatives with wide possibilities for derivatization, we explored the isocyanate cyclization procedure and we synthesized a bcarboline scaffold with an amino group in position C6 and a 2-hydroxyethyl group at C4 (Scheme 2).Starting from known 5-nitro-1H-indole-2-carbaldehyde, 10 Wittig reaction with ethyl (triphenylphosphanylidene)acetate afforded the a,b-unsaturated ester 9 as 9:1 mixture of E/Z isomers in excellent yield. The 3-(2-aminoethyl) appendage needed for the cyclization to the b-carboline scaffold was introduced through a Michael addition of nitromethane followed by reduction of the nitro group. In order to avoid the simultaneous presence of two nitro groups, the aromatic substituent was reduced and the amine protected prior to the Michael addition. Moreover, the indole nitrogen had to be protected with an electronwithdrawing tert-butoxycarbonyl group, since attempts to perform the conjugate addition reaction on the unprotected indole failed, presumably due to electron delocalization (Scheme 3).