Craig E. Masse

Accurate and Reliable Prediction of Relative Ligand Binding Potency in Prospective Drug Discovery by Way of a Modern Free-Energy Calculation Protocol and Force Field

Designing tight-binding ligands is a primary objective of small-molecule drug discovery. Over the past few decades, free-energy calculations have benefited from improved force fields and sampling algorithms, as well as the advent of low-cost parallel computing. However, it has proven to be challenging to reliably achieve the level of accuracy that would be needed to guide lead optimization (∼5× in binding affinity) for a wide range of ligands and protein targets. Not surprisingly, widespread commercial application of free-energy simulations has been limited due to the lack of large-scale validation coupled with the technical challenges traditionally associated with running these types of calculations. Here, we report an approach that achieves an unprecedented level of accuracy across a broad range of target classes and ligands, with retrospective results encompassing 200 ligands and a wide variety of chemical perturbations, many of which involve significant changes in ligand chemical structures. In addition, we have applied the method in prospective drug discovery projects and found a significant improvement in the quality of the compounds synthesized that have been predicted to be potent. Compounds predicted to be potent by this approach have a substantial reduction in false positives relative to compounds synthesized on the basis of other computational or medicinal chemistry approaches. Furthermore, the results are consistent with those obtained from our retrospective studies, demonstrating the robustness and broad range of applicability of this approach, which can be used to drive decisions in lead optimization.

TOTAL SYNTHESIS OF (+)-LACTACYSTIN

A double stereodifferentiating crotylation between aldehyde 1 and silane (S)-2 to afford homoallylic alcohol 3 is the key diastereoselective step (anti:syn >30:1) in an efficient asymmetric synthesis of (+)-lactacystin. This compound is a metabolite isolated from Streptomyces sp. OM-6519 that exhibits significant neurotrophic activity. An additional important step in the synthesis is a catalytic asymmetric aminohydroxylation used as the key step in the synthesis of the (2R,3S)-hydroxyleucine synthon.

Syntheses and Biological Evaluation of (+)‐Lactacystin and Analogs

Since its isolation in 1991, (+)-lactacystin (1) has attracted considerable attention among leading synthesis laboratories due to its highly selective and potent inhibition of the 20S proteasome. The syntheses of this molecule described herein demonstrate several important strategies in the area of acyclic stereocontrol including the use of chiral metal enolate and chiral allylmetal-based bond construction methods. Several analogs of 1 and of the related β-lactone 2 are also presented, which provide insight into the structure activity relationship relative to the molecule’s inhibition of the 20S proteasome. Additionally, an analog of 2 is discussed regarding its clinical evaluation for the treatment of cerebral ischemia and stroke.

Accelerating drug discovery through tight integration of expert molecular design and predictive scoring

Modeling protein-ligand interactions has been a central goal of computational chemistry for many years. We here review recent progress toward this goal, and highlight the role free energy calculation methods and computational solvent analysis techniques are now having in drug discovery. We further describe recent use of these methodologies to advance two separate drug discovery programs targeting acetyl-CoA carboxylase and tyrosine kinase 2. These examples suggest that tight integration of sophisticated chemistry teams with state-of-the-art computational methods can dramatically improve the efficiency of small molecule drug discovery.

Eine effiziente Totalsynthese von (+)‐Lactacystin

Eine doppelt stereodifferenzierende Crotylierung des Aldehyds 1 mit dem Silan (S)-2 zum Homoallylalkohol 3 ist der diastereoselektive Schlusselschritt (anti:syn >30:1) einer effizienten asymmetrischen Synthese von (+)-Lactacystin. (+)-Lactacystin ist ein aus Streptomyces sp. OM-6519 isolierter Metabolit mit bemerkenswerter neurotropher Aktivitat. Ein weiterer wichtiger Schritt der Synthese ist eine katalytische asymmetrische Aminohydroxylierung als entscheidender Schritt bei der Synthese des (2R,3S)-Hydroxyleucin-Synthons.

Anti-leukaemic activity of the TYK2 selective inhibitor NDI-031301 in T-cell acute lymphoblastic leukaemia

Activation of tyrosine kinase 2 (TYK2) contributes to the aberrant survival of T‐cell acute lymphoblastic leukaemia (T‐ALL) cells. Here we demonstrate the anti‐leukaemic activity of a novel TYK2 inhibitor, NDI‐031301. NDI‐031301 is a potent and selective inhibitor of TYK2 that induced robust growth inhibition of human T‐ALL cell lines. NDI‐031301 treatment of human T‐ALL cell lines resulted in induction of apoptosis that was not observed with the JAK inhibitors tofacitinib and baricitinib. Further investigation revealed that NDI‐031301 treatment uniquely leads to activation of three mitogen‐activated protein kinases (MAPKs), resulting in phosphorylation of ERK, SAPK/JNK and p38 MAPK coincident with PARP cleavage. Activation of p38 MAPK occurred within 1 h of NDI‐031301 treatment and was responsible for NDI‐031301‐induced T‐ALL cell death, as pharmacological inhibition of p38 MAPK partially rescued apoptosis induced by TYK2 inhibitor. Finally, daily oral administration of NDI‐031301 at 100 mg/kg bid to immunodeficient mice engrafted with KOPT‐K1 T‐ALL cells was well tolerated, and led to decreased tumour burden and a significant survival benefit. These results support selective inhibition of TYK2 as a promising potential therapeutic strategy for T‐ALL.