DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance.

Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD.

Discovery of New Binders for DCAF1, an Emerging Ligase Target in the Targeted Protein Degradation Field.

In this study, we describe the rapid identification of potent binders for the WD40 repeat domain (WDR) of DCAF1. This was achieved by two rounds of iterative focused screening of a small set of compounds selected on the basis of internal WDR domain knowledge followed by hit expansion. Subsequent structure-based design led to nanomolar potency binders with a clear exit vector enabling DCAF1-based bifunctional degrader exploration.

Synthesis of the Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor NB-360.

Starting from lead compound , the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF group delivered an excellent pharmacological profile with a p of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure.

p53 dynamics vary between tissues and are linked with radiation sensitivity.

Radiation sensitivity varies greatly between tissues. The transcription factor p53 mediates the response to radiation; however, the abundance of p53 protein does not correlate well with the extent of radiosensitivity across tissues. Given recent studies showing that the temporal dynamics of p53 influence the fate of cultured cells in response to irradiation, we set out to determine the dynamic behavior of p53 and its impact on radiation sensitivity in vivo.

Structural States of Hdm2 and HdmX: X-ray Elucidation of Adaptations and Binding Interactions for Different Chemical Compound Classes.

Hdm2 (human MDM2, human double minute 2 homologue) counteracts p53 function by direct binding to p53 and by ubiquitin-dependent p53 protein degradation. Activation of p53 by inhibitors of the p53-Hdm2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. In addition, HdmX (human MDMX, human MDM4) was also identified as an important therapeutic target to efficiently reactivate p53, and it is likely that dual inhibition of Hdm2 and HdmX is beneficial.

In vitro and in vivo characterization of a novel, highly potent p53-MDM2 inhibitor.

Small molecule inhibitors of the p53-MDM2 protein complex are under intense investigation in clinical trials as anti-cancer agents, including our first generation inhibitor NVP-CGM097. We recently described the rational design of a novel pyrazolopyrrolidinone core as a new lead structure and now we report on the synthesis and optimization of this to provide a highly potent lead compound. This new compound displayed excellent oral efficacy in our preclinical mechanistic in vivo model and marked a significant milestone towards the identification of our second generation clinical candidate NVP-HDM201.

Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53-MDM2 Inhibitor HDM201.

Activation of p53 by inhibitors of the p53-MDM2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. Here, we report distinct mechanisms by which the novel, potent, and selective inhibitor of the p53-MDM2 interaction HDM201 elicits therapeutic efficacy when applied at various doses and schedules. Continuous exposure of HDM201 led to induction of p21 and delayed accumulation of apoptotic cells.

Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors.

New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays.

Discovery of Potent and Selective p53-MDM2 Protein-Protein Interaction Inhibitors as Anticancer Drugs.

As a result of our persistent efforts to discover novel inhibitors of the p53-MDM2 protein-protein interaction useful for the treatment of cancer, the potent and selective MDM2 inhibitors NVP-CGM097 and NVP-HDM201 with excellent in vitro and in vivo profile were selected as clinical candidates and are currently in phase 1 clinical development. This short review article provides a summary of the program history, the applied pharmacophore model and the discovery story of these novel p53-MDM2 inhibitor investigational drugs.

Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.

Misdirected catalytic activity of histone methyltransferase Dot1L is believed to be causative for a subset of highly aggressive acute leukemias. Targeting the catalytic domain of Dot1L represents a potential therapeutic approach for these leukemias. In the context of a comprehensive Dot1L hit finding strategy, a knowledge-based virtual screen of the Dot1L SAM binding pocket led to the discovery of , a non-nucleoside fragment mimicking key interactions of SAM bound to Dot1L.

Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach.

Oncogenic MLL fusion proteins aberrantly recruit Dot1L, a histone methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of Dot1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to repression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the identification of 2, a weak Dot1L inhibitor with an unprecedented, induced pocket binding mode.

Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument.

The p53-MDM2 interaction is an anticancer drug target under investigation in the clinic. Our compound NVP-CGM097 is one of the small molecule inhibitors of this protein-protein interaction currently evaluated in cancer patients. As part of our effort to identify new classes of p53-MDM2 inhibitors that could lead to additional clinical candidates, we report here the design of highly potent inhibitors having a pyrazolopyrrolidinone core structure.

Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors.

As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species.

Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode.

Blocking the interaction between the p53 tumor suppressor and its regulatory protein MDM2 is a promising therapeutic concept under current investigation in oncology drug research. We report here the discovery of the first representatives of a new class of small molecule inhibitors of this protein-protein interaction: the dihydroisoquinolinones. Starting from an initial hit identified by virtual screening, a derivatization program has resulted in compound 11, a low nanomolar inhibitor of the p53-MDM2 interaction showing significant cellular activity.

A distinct p53 target gene set predicts for response to the selective p53-HDM2 inhibitor NVP-CGM097.

Biomarkers for patient selection are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report the discovery of a novel patient selection strategy for the p53-HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By intersecting high-throughput cell line sensitivity data with genomic data, we have identified a gene expression signature consisting of 13 up-regulated genes that predicts for sensitivity to NVP-CGM097 in both cell lines and in patient-derived tumor xenograft models.

Tunable vacuum-UV to visible ultrafast pulse source based on gas-filled Kagome-PCF.

An efficient and tunable 176-550 nm source based on the emission of resonant dispersive radiation from ultrafast solitons at 800 nm is demonstrated in a gas-filled hollow-core photonic crystal fiber (PCF). By careful optimization and appropriate choice of gas, informed by detailed numerical simulations, we show that bright, high quality, localized bands of UV light (relative widths of a few percent) can be generated at all wavelengths across this range. Pulse energies of more than 75 nJ in the deep-UV, with relative bandwidths of ~3%, are generated from pump pulses of a few μJ.

Podocyte EphB4 signaling helps recovery from glomerular injury.

Eph receptor tyrosine kinases and their ligands (ephrins) have a pivotal role in the homeostasis of many adult organs and are widely expressed in the kidney. Glomerular diseases beginning with mesangiolysis can recover, with podocytes having a critical role in this healing process. We studied here the role of Eph signaling in glomerular disease recovery following mesangiolytic Thy1.

Theory of photoionization-induced blueshift of ultrashort solitons in gas-filled hollow-core photonic crystal fibers.

We show theoretically that the photoionization process in a hollow-core photonic crystal fiber filled with a Raman-inactive noble gas leads to a constant acceleration of solitons in the time domain with a continuous shift to higher frequencies, limited only by ionization loss. This phenomenon is opposite to the well-known Raman self-frequency redshift of solitons in solid-core glass fibers. We also predict the existence of unconventional long-range nonlocal soliton interactions leading to spectral and temporal soliton clustering.

The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis.

EphB4 and its cognitive ligand ephrinB2 play an important role in embryonic vessel development and vascular remodeling. In addition, several reports suggest that this receptor ligand pair is also involved in pathologic vessel formation in adults including tumor angiogenesis. Eph/ephrin signaling is a complex phenomena characterized by receptor forward signaling through the tyrosine kinase of the receptor and ephrin reverse signaling through various protein-protein interaction domains and phosphorylation motifs of the ephrin ligands.

Discovery and SAR of potent, orally available 2,8-diaryl-quinoxalines as a new class of JAK2 inhibitors.

We have designed and synthesized a novel series of 2,8-diaryl-quinoxalines as Janus kinase 2 inhibitors. Many of the inhibitors show low nanomolar activity against JAK2 and potently suppress proliferation of SET-2 cells in vitro. In addition, compounds from this series have favorable rat pharmacokinetic properties suitable for in vivo efficacy evaluation.

2-Amino-aryl-7-aryl-benzoxazoles as potent, selective and orally available JAK2 inhibitors.

A series of novel benzoxazole derivatives has been designed and shown to exhibit attractive JAK2 inhibitory profiles in biochemical and cellular assays, capable of delivering compounds with favorable PK properties in rats. Synthesis and structure-activity relationship data are also provided.

Blocking the PI3K/PKB pathway in tumor cells.

A substantial number of experimental and epidemiological studies support an important role for the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) pathway in the biology of human cancers. Components of this signaling cascade have been found to be deregulated in a wide range of solid tumors and hematologic malignancies, and extensive anti-cancer therapeutic programs are now devoted to the identification of agents that specifically block this molecular pathway. This article focuses on the current knowledge of the alterations of the PI3K/PKB pathway in cancer cells and ongoing drug discovery efforts to therapeutically target it.

A supramolecular enzyme model catalyzing the central cleavage of carotenoids.

Several bis-beta-cyclodextrin porphyrins have been prepared as supramolecular receptors of carotenoids. The binding constants of carotenoids to receptors were determined by quenching the fluorescence of the porphyrins on hydrophobic binding of carotenoids within the cavities of cyclodextrins. K(a)=8.