Kareem Khoury

Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists.

Although there is no shortage of potential drug targets, there are only a handful known low-molecular-weight inhibitors of protein-protein interactions (PPIs). One problem is that current efforts are dominated by low-yield high-throughput screening, whose rigid framework is not suitable for the diverse chemotypes present in PPIs. Here, we developed a novel pharmacophore-based interactive screening technology that builds on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel compounds. Application of this approach to the MDM2/p53 cancer target led to high hit rates, resulting in a large and diverse set of confirmed inhibitors, and co-crystal structures validate the designed compounds. Our unique open-access technology promises to expand chemical space and the exploration of the human interactome by leveraging in-house small-scale assays and user-friendly chemistry to rationally design ligands for PPIs with known structure.

Efficient Assembly of Iminodicarboxamides by a “Truly” Four-Component Reaction†

A truly 4-component reaction! In analogy to a galaxy consisting of millions of stars a multicomponent reaction scaffold can result in millions of compound variations. The MCR of α-amino acids, oxocomponents, isocyanides and primary or secondary amines is such a high-number high-diversity reaction providing an enormous potential for drug discovery or catalyst screening.

The p53-MDM2/MDMX axis – A chemotype perspective

The protein-protein interaction (PPI) of the tumor suppressor p53 and its negative regulator MDM2 consists of the most intense studied PPI with a group of small molecular weight antagonists described and many more disclosed in patent literature. Due to the Å-level structural insight into p53 interaction with MDM2 there is a reasonable understanding of the requirements of the molecules to bind. In contrast and despite the very close homology and 3-D similarity no potent MDMX antagonist has been disclosed up to date. The current review summarizes the different disclosed chemotypes for MDM2 including a discussion of the cocrystal structures. Structures and approaches to reconstitute functional p53 from mutated p53 are presented. Finally new screening methods and recent biotech deals based on p53 are discussed.

Multicomponent Synthesis of Diverse 1,4-Benzodiazepine Scaffolds

The 1,4-benzodiazepine (BDZ) scaffold is of particular interest in drug design due to a balanced ensemble of beneficial physicochemical properties including a semirigid and compact diazepine ring with spatial placements of several substituents, combined with low number of rotatable bonds, hydrogen bond donors and acceptors, and intermediate lipophilicity. As an alternative to traditional multistep sequential syntheses, we designed routes employing one-pot MCRs to accelerate access diverse BDZ scaffolds in two or three steps.

Discovery of Highly Potent p53-MDM2 Antagonists and Structural Basis for Anti-Acute Myeloid Leukemia Activities

The inhibition of p53-MDM2 interaction is a promising new approach to non-genotoxic cancer treatment. A potential application for drugs blocking the p53-MDM2 interaction is acute myeloid leukemia (AML) due to the occurrence of wild type p53 (wt p53) in the majority of patients. Although there are very promising preclinical results of several p53-MDM2 antagonists in early development, none of the compounds have yet proven the utility as a next generation anticancer agent. Herein we report the design, synthesis and optimization of YH239-EE (ethyl ester of the free carboxylic acid compound YH239), a potent p53-MDM2 antagonizing and apoptosis-inducing agent characterized by a number of leukemia cell lines as well as patient-derived AML blast samples. The structural basis of the interaction between MDM2 (the p53 receptor) and YH239 is elucidated by a co-crystal structure. YH239-EE acts as a prodrug and is the most potent compound that induces apoptosis in AML cells and patient samples. The observed superior activity compared to reference compounds provides the preclinical basis for further investigation and progression of YH239-EE.

Various cyclization scaffolds by a truly Ugi 4-CR

Efficient access to a large chemical space based on new scaffolds with defined 3D conformations and highly variable in the side chains is needed to find novel functional materials. Four heterocyclic scaffolds based on a four component Ugi reaction of α-amino acids, oxo components, isocyanides and primary or secondary amines suitably functionalized are described. A handful of examples are described for each scaffold.

P53 Mdm2 Inhibitors

The protein-protein interaction (PPI) between p53 and its negative regulator MDM2 comprises one of the most important and intensely studied PPIs involved in preventing the initiation of cancer. The interaction between p53 and MDM2 is conformation-based and is tightly regulated on multiple levels. Due to the Angstrom level structural insight there is a reasonable understanding of the structural requirements needed for a molecule to bind to MDM2 and successfully inhibit the p53/MDM2 interaction. The current review summarizes the binding characteristics of the different disclosed small molecules for inhibition of MDM2 with a co-crystal structure. Synthetic access to these compounds as well as their derivatives are described in detail.

Tricycles by a new Ugi variation and Pictet-Spengler reaction in one pot.

Subsequent mild cyclization of aromatic substrates by Pictet-Spengler condensation stereoselectively gave new tricyclic compounds. Examples are described in decent yields over two steps in one pot, and a crystal structure is also presented to support the proposed structures.

MCR synthesis of a tetracyclic tetrazole scaffold

Scaffold diversity is key in the ongoing exercise of discovery of novel bioactive compounds using high throughput screening (HTS). Based on the Ugi tetrazole synthesis we have designed novel bi- and tri-cyclic scaffolds featuring interesting pharmacophore properties. The compounds of the scaffold (B) are synthesizable in large diversity and numbers in two steps using (hetero)phenylethylamines, HN3, oxo components and iscyanoacetaldehyde(dimethylacetale). The chemistry is amenable to parallel synthesis and is used to enhance and fill the screening decks of the European Lead factory (ELF). Here, we are reporting full experimental details, scope and limitations of the reaction, cheminformatic analysis and the 3D structures of selected compounds.

A universal isocyanide for diverse heterocycle syntheses.

Novel scaffolds are of uttermost importance for the discovery of functional material. Three different heterocyclic scaffolds easily accessible from isocyanoacetaldehyde dimethylacetal 1 by multicomponent reaction (MCR) are described. They can be efficiently synthesized by a Ugi tetrazole multicomponent reaction of 1. We discuss the synthesis, 3D structures, and other physicochemical properties.