David Joseph Bartkovitz

Discovery of RG7388, a Potent and Selective p53–MDM2 Inhibitor in Clinical Development

Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.

Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development

The development of small-molecule MDM2 inhibitors to restore dysfunctional p53 activities represents a novel approach for cancer treatment. In a previous communication, the efforts leading to the identification of a non-imidazoline MDM2 inhibitor, RG7388, was disclosed and revealed the desirable in vitro and in vivo pharmacological properties that this class of pyrrolidine-based inhibitors possesses. Given this richness and the critical need for a wide variety of chemical structures to ensure success in the clinic, research was expanded to evaluate additional derivatives. Here we report two new potent, selective, and orally active p53-MDM2 antagonists, RO5353 and RO2468, as follow-ups with promising potential for clinical development.

Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy

The field of small-molecule inhibitors of protein-protein interactions is rapidly advancing and the specific area of inhibitors of the p53/MDM2 interaction is a prime example. Several groups have published on this topic and multiple compounds are in various stages of clinical development. Building on the strength of the discovery of RG7112, a Nutlin imidazoline-based compound, and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds that provide opportunities for future development. Here, we report the discovery and optimization of a highly potent and selective series of spiroindolinone small-molecule MDM2 inhibitors, culminating in RO8994.

Identification of novel, potent and selective inhibitors of Polo-like kinase 1.

A series of pyrimidodiazepines was identified as potent Polo-like kinase 1 (PLK1) inhibitors. The synthesis and SAR are discussed. The lead compound 7 (RO3280) has potent inhibitory activity against PLK1, good selectivity against other kinases, and excellent in vitro cellular potency. It showed strong antitumor activity in xenograft mouse models.

Highly Selective Cyclic Peptides for Human Melanocortin-4 Receptor (MC-4 R): Design, Synthesis, Bioactive Conformation, and Pharmacological Evaluation as an Anti-Obesity Agent

Melanocortin (MC) peptides α-, β-, and γ-MSH and adreno-corticotropic hormone (ACTH) are a group of neuropeptides derived from pro-opiomelanocortin hormone (POMC). The physiological actions of these peptides are mediated through five (MCR-1–5) seven-transmembrane G-protein-coupled receptor subtypes. The MSH peptides have been implicated in numerous biological functions [1] including regulation of skin pigmentation, regulation of steroid production, modulation of the immune response, thermo-regulation and obesity [2]. Clarification of the role of melanocortin receptor subtypes, in particular the recently discovered MC-3, MC-4 and MC-5 receptors, has been hampered by the lack of selective peptide ligands. However, recent studies on MCR knockout animals demonstrated that the MC-4 receptor is involved in regulation of feeding. MCR-4 knockout mice display an obesity phenotype that includes maturity onset obesity, hyperglycemia, and hyperinsulinemia. Moreover, it has been reported that a non-selective cyclic MCR-4 peptide agonist (MT II) inhibits food intake when given icv to mice [3]. Consequently, a potent and selective MC-4R agonist is regarded as potentially useful in therapeutic approaches to obesity management. The goal of this work was to identify a selective MCR-4 cyclic peptide agonist for use as a pharmacological tool in obesity and feeding studies and to develop a pharmacophore model applicable to structure-based drug design.