Nicholas Alexander Till

Bio: Nicholas Alexander Till is an academic researcher. The author has contributed to research in topics: Axial chirality & Aldehyde oxidase. The author has an hindex of 1, co-authored 2 publications receiving 24 citations.

Atropisomerism by Design: Discovery of a Selective and Stable Phosphoinositide 3-Kinase (PI3K) β Inhibitor

Abstract: Atropisomerism is a type of axial chirality in which enantiomers or diastereoisomers arise due to hindered rotation around a bond axis. In this manuscript, we report a case in which torsional scan studies guided the thoughtful creation of a restricted axis of rotation between two heteroaromatic systems of a phosphoinositide 3-kinase (PI3K) β inhibitor, generating a pair of atropisomeric compounds with significantly different pharmacological and pharmacokinetic profiles. Emblematic of these differences, the metabolism of inactive (M)-28 is primarily due to the cytosolic enzyme aldehyde oxidase, while active (P)-28 has lower affinity for aldehyde oxidase, resulting in substantially better metabolic stability. Additionally, we report torsional scan and experimental studies used to determine the barriers of rotation of this novel PI3Kβ inhibitor.

Discovery of an Atropisomeric PI3Kβ Selective Inhibitor through Optimization of the Hinge Binding Motif

Abstract: A series of PI3Kβ selective inhibitors derived from a novel 4-(1H-benzo[d]imidazol-1-yl)quinoline chemotype has been rationally designed. Crucial to achieving the desired selectivity over the other class I PI3K isoforms, including the challenging δ-isoform, was the identification of a subset of substituted pyridine hinge binders. This work led to the discovery of (P)-14, a highly selective and orally bioavailable PI3Kβ inhibitor displaying an excellent pharmacokinetic profile in addition to great cellular potency in various PTEN-deficient tumor cell lines. Results from a dog toxicology study revealing structure-related, off-target ocular toxicity are also briefly discussed.

PI3K inhibitors are finally coming of age.

Abstract: Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval — the PI3Kα isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3Kδ in B cell malignancies. In addition to targeting cancer cell-intrinsic PI3K activity, emerging evidence highlights the potential of PI3K inhibitors in cancer immunotherapy. This Review summarizes key discoveries that aid the clinical translation of PI3Kα and PI3Kδ inhibitors, highlighting lessons learnt and future opportunities PI3K signalling is one of the most frequently aberrantly activated pathways in cancer. However, the development of therapeutic PI3K pathway inhibitors has faced challenges including poor drug tolerance and drug resistance. Here, Vanhaesebroeck et al. review efforts to understand and therapeutically exploit the biology of PI3Kα and PI3Kδ — the key targets of currently approved PI3K inhibitors, highlighting lessons learned and future opportunities.

Enantioselective Synthesis of N-C Axially Chiral Compounds by Cu-Catalyzed Atroposelective Aryl Amination.

Abstract: N-C axially chiral compounds have emerged recently as appealing motifs for drug design. However, the enantioselective synthesis of such molecules is still poorly developed and surprisingly no metal-catalyzed atroposelective N-arylations have been described. Herein, we disclose an unprecedented Cu-catalyzed atroposelective N-C coupling that proceeds at room temperature. Such mild reaction conditions, which are a crucial parameter for atropostability of the newly generated products, are operative thanks to the use of hypervalent iodine reagents as a highly reactive coupling partners. A large panel of the N-C axially chiral compounds was afforded with very high enantioselectivity (up to >99 % ee) and good yields (up to 76 %). Post-modifications of thus accessed atropisomeric compounds allows further expansion of the diversity of these appealing compounds.

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

Abstract: Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ have unique, non-redundant physiological roles and as such, isoform selectivity has been a key consideration driving inhibitor design and development. In this review, we discuss the structural biology of PI3Ks and how our growing knowledge of structure has influenced the medicinal chemistry of PI3K inhibitors. We present an analysis of the available structure-selectivity-activity relationship data to highlight key insights into how the various regions of the PI3K binding site influence isoform selectivity. The picture that emerges is one that is far from simple and emphasizes the complex nature of protein-inhibitor binding, involving protein flexibility, energetics, water networks and interactions with non-conserved residues.

Metabolism by Aldehyde Oxidase: Drug Design and Complementary Approaches to Challenges in Drug Discovery

Abstract: Aldehyde oxidase (AO) catalyzes oxidations of azaheterocycles and aldehydes, amide hydrolysis, and diverse reductions. AO substrates are rare among marketed drugs, and many candidates failed due to poor pharmacokinetics, interspecies differences, and adverse effects. As most issues arise from complex and poorly understood AO biology, an effective solution is to stop or decrease AO metabolism. This perspective focuses on rational drug design approaches to modulate AO-mediated metabolism in drug discovery. AO biological aspects are also covered, as they are complementary to chemical design and important when selecting the experimental system for risk assessment. The authors' recommendation is an early consideration of AO-mediated metabolism supported by computational and in vitro experimental methods but not an automatic avoidance of AO structural flags, many of which are versatile and valuable building blocks. Preferably, consideration of AO-mediated metabolism should be part of the multiparametric drug optimization process, with the goal to improve overall drug-like properties.