Identification of Atuveciclib (BAY 1143572), the First Highly Selective, Clinical PTEFb/CDK9 Inhibitor for the Treatment of Cancer

Abstract

Selective inhibition of exclusively transcription‐regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY‐958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited the best overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats. BAY 1143572 is the first potent and highly selective PTEFb/CDK9 inhibitor to enter clinical trials for the treatment of cancer.

Novel Pieces for the Emerging Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical Candidates

“…[a] IC 50 values determined in biochemical in vitro kinase assays in the presence of 10 μ m ATP . [b] IC 50 values determined in an in vitro proliferation assay using cultivated A2780 cells .…”

“…[a] IC 50 values determined in biochemical in vitro kinase assays in the presence of 10 μ m ATP . [b] IC 50 values determined in an in vitro proliferation assay using cultivated A2780 cells . [c] Thermodynamic solubility in water determined by an equilibrium shake flask method; solid state of the test compounds was not characterized.…”

“…[a] IC 50 values determined in a PDE5 enzyme assay using [ 3 H]‐cGMP as substrate, measured via a scintillation proximity assay technique . [b] Thermodynamic solubility in water determined by an equilibrium shake flask method; solid state of the test compounds was not characterized. [c] Determined by reversed‐phase HPLC .…”

3D Heterocycles from Sulfonimidamides by Sequential C−H Bond Alkenylation/Aza‐Michael Cyclization

“…Sulfur is one of the most frequently occurring elements in bioactive molecules . Thus, it is surprising that beside the well‐studied sulfones and sulfonamides other related classes of sulfur compounds, such as sulfoximines, sulfondiimines, and sulfonimidamides have only scarcely been considered for applications in medicinal chemistry and crop protection. Our group has a long‐standing interest in exploring the aforementioned compound classes, also with the aim to expand the chemical space towards 3D sulfur‐containing heterocycles, such as benzothiazines and 1‐oxides of isothiazoles and thiazines, as well as thiadiazines and benzothiazepines .…”

Increasing Complexity: A Practical Synthetic Approach to Three‐Dimensional, Cyclic Sulfoximines and First Insights into Their in Vitro Properties

“…Sulfoximines 2 , the mono‐aza analogues of sulfones 1 , have only recently been the subject of growing interest in drug discovery (Figure ) . Nevertheless, four sulfoximine compounds (roniciclib, atuveciclib, BAY 1251152, and AZD6738) have entered clinical evaluation for the treatment of cancer of late, and their promising physicochemical and DMPK properties were important triggers for their selection as clinical candidates. Sulfoximines 2 are isoelectronic with sulfones 1 , but introduction of the nitrogen atom creates asymmetry at the tetrahedral sulfur atom if the two carbon substituents R 1 and R 2 are not identical.…”