Discovery of quinazoline HPK1 inhibitors with high cellular potency.

Hematopoietic progenitor kinase 1 (HPK1) is regarded as a highly validated target in pre-clinical immune oncology. HPK1 has been described as regulating multiple critical signaling pathway in both adaptive and innate cells. In support of this role, HPK1 KO T cells show enhanced sensitivity to TCR activation and HPK1 KO mice display enhanced anti-tumor activity. Taken together, inhibition of HPK1 has the potential to induce enhanced anti-tumor immune response. Herein, we described the discovery of highly potent HPK1 inhibitors starting form a weak HTS hit. Using a structure-based drug design, HPK1 inhibitors exhibiting excellent cellular single-digit nanomolar potency in both proximal (pSLP76) and distal (IL-2) biomarkers along with sustained elevation of IL-2 cytokine secretion were discovered.

Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects.

Accurate ranking of compounds with regards to their binding affinity to a protein using computational methods is of great interest to pharmaceutical research. Physics-based free energy calculations are regarded as the most rigorous way to estimate binding affinity. In recent years, many retrospective studies carried out both in academia and industry have demonstrated its potential. Here, we present the results of large-scale prospective application of the FEP+ method in active drug discovery projects in an industry setting at Merck KGaA, Darmstadt, Germany. We compare these prospective data to results obtained on a new diverse, public benchmark of eight pharmaceutically relevant targets. Our results offer insights into the challenges faced when using free energy calculations in real-life drug discovery projects and identify limitations that could be tackled by future method development. The new public data set we provide to the community can support further method development and comparative benchmarking of free energy calculations.

Enantioselective aziridination of cyclic enals facilitated by the fluorine-iminium ion gauche effect.

The enantioselective, organocatalytic aziridination of small, medium and macro-cyclic enals is reported using (S)-2-(fluorodiphenyl methyl)-pyrrolidine. Central to the reaction design is the reversible formation of a ß-fluoroiminium ion intermediate, which is pre-organised on account of the fluorine-iminium ion gauche effect. This conformational effect positions the fluorine substituent synclinal-endo to the electropositive nitrogen centre thus benefiting from favourable stereoelectronic and electrostatic interactions (σC-H →σC-F *; F(δ-…︁) N(+) ). Consequently, one of the shielding groups on the fluorine-bearing carbon atom is positioned above the π-system, forming the basis of an enantioinduction strategy. Treatment of this intermediate with a "nitrene" source furnished a series of novel, optically active aziridines (e.r. up to 99.5:0.5). Further derivatisation of the product aziridines gives facile access to various amino acid derivatives, including ß-fluoroamino acids. Crystallographic analyses of both the aziridines and their derivatives are disclosed.

Chemistry without bo(a)rders.

Note from the Editor: Science, collegiality, travel without borders. Big smiles and warmth. Eternally youthful vigor. When I think of Tetsuo Nozoe, these are the images that immediately come to mind. When I think of the Nozoe Autograph Books, I also think of time. For 40 years, Nozoe carried with him his autograph books and collected his treasures which The Chemical Record is now publishing. Vladimir Prelog signed first when he was 47 and signed last when he was almost 80. Derek Barton signed first when he was 35 and signed last when he was almost 70. Time! I was fascinated by Eva Wille's recommendation that we publish an essay by Eva-Maria Tanzer, a young organic chemist with already a lifetime's experience in exploring chemical research in laboratories around the world. Tanzer brings to us a charming, even innocent perspective that embraces so much of Tetsuo Nozoe's ideals. We are privileged to include Tanzer's vision and her experiences in the collection of essays that accompany the Nozoe Autograph Books. Our contributors range in age and experiences, from the youthful Tanzer to the more mature (including myself!) as do the signatories in the autograph books. Tetsuo Nozoe would have beamed!--Jeffrey I. Seeman Guest Editor University of Richmond Richmond, Virginia 23173, USA E-mail: jseeman@richmond.edu.

Designing fluorinated cinchona alkaloids for enantioselective catalysis: controlling internal rotation by a fluorine-ammonium ion gauche effect (φ(NCCF)).

The C9 position of cinchona alkaloids functions as a molecular hinge, with internal rotations around the C8-C9 (τ(1)) and C9-C4' (τ(2)) bonds giving rise to four low energy conformers (1; anti-closed, anti-open, syn-closed, and syn-open). By substituting the C9 carbinol centre by a configurationally defined fluorine substituent, a fluorine-ammonium ion gauche effect (σ(C-H) → σ(C-F)*; F(δ-)⋅⋅⋅N(+)) encodes for two out of the four possible conformers (2). This constitutes a partial solution to the long-standing problem of governing internal rotations in cinchonium-based catalysts relying solely on a fluorine conformational effect.

Fluorinated organocatalysts for the enantioselective epoxidation of enals: molecular preorganisation by the fluorine-iminium ion gauche effect.

The fluorine-iminium ion gauche effect is triggered upon union of a secondary ß-fluoroamine and an α,ß-unsaturated aldehyde, providing a useful strategy for controlling the molecular topology of intermediates that are central to organocatalytic processes. The ß-fluoroamine (S)-2-(fluorodiphenylmethyl)pyrrolidine (1) is an effective catalyst for the enantioselective epoxidation of α,ß-unsaturated aldehydes. A process of structural editing has revealed that the efficiency of this catalyst is due to the (fluorodiphenyl)methyl group when it is embedded in a ß-fluoroiminium motif. Epoxidations of challenging cyclic α,ß-disubstituted, ß,ß-disubstituted and α,ß,ß-trisubstituted enals catalysed by 1 proceed with excellent levels of enantiocontrol (up to 98% ee).

A novel one-pot procedure for the stereoselective synthesis of alpha-hydroxy esters from ortho esters.

A novel one-pot procedure for the stereoselective synthesis of alpha-hydroxy esters from ortho esters was developed. Key steps were multi-heteroatom Cope rearrangements of O-acylated N-hydroxy-l-tert-leucinol-derived oxazoline N-oxides leading to alpha-acyloxy oxazolines and, after methanolysis, to the target molecules in 67-80% yield and 94-98% ee.