The phosphoinositide 3‐kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and ...amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3‐dihydroimidazo1,2‐cquinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kβ. Herein, initial structure–activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80‐6946) as a clinical candidate for the treatment of solid and hematological tumors are described.
The phosphoinositide 3‐kinase (PI3K) pathway is aberrantly activated in many tumors. The presence of various PI3K isoforms and their differential roles in cancers makes them ideal candidates for targeted inhibition. A PI3Kγ screening hit led to the discovery of the novel 2,3‐dihydroimidazo1,2‐cquinazoline class of PI3K inhibitors. Herein we describe initial structure–activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80‐6946) as a clinical candidate.
Thymidylate kinase (TMK), an essential enzyme in bacterial DNA biosynthesis, is an attractive therapeutic target for the development of novel antibacterial agents, and we continue to explore TMK ...inhibitors with improved potency, protein binding, and pharmacokinetic potential. A structure-guided design approach was employed to exploit a previously unexplored region in Staphylococcus aureus TMK via novel interactions. These efforts produced compound 39, with 3 nM IC50 against S. aureus TMK and 2 μg/mL MIC against methicillin-resistant S. aureus (MRSA). This compound exhibits a striking inverted chiral preference for binding relative to earlier compounds and also has improved physical properties and pharmacokinetics over previously published compounds. An example of this new series was efficacious in a murine S. aureus infection model, suggesting that compounds like 39 are options for further work toward a new Gram-positive antibiotic by maintaining a balance of microbiological potency, low clearance, and low protein binding that can result in lower efficacious doses.
Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in a rational-design, structure-supported ...effort, yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by X-ray crystallography, led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs < 1 μg/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-positive bacteria and excellent selectivity against the human thymidylate kinase ortholog.
There is an urgent need for new antibacterials that pinpoint novel targets and thereby avoid existing resistance mechanisms. We have created novel synthetic antibacterials through structure-based ...drug design that specifically target bacterial thymidylate kinase (TMK), a nucleotide kinase essential in the DNA synthesis pathway. A high-resolution structure shows compound TK-666 binding partly in the thymidine monophosphate substrate site, but also forming new induced-fit interactions that give picomolar affinity. TK-666 has potent, broad-spectrum Gram-positive microbiological activity (including activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus), bactericidal action with rapid killing kinetics, excellent target selectivity over the human ortholog, and low resistance rates. We demonstrate in vivo efficacy against S. aureus in a murine infected-thigh model. This work presents the first validation of TMK as a compelling antibacterial target and provides a rationale for pursuing novel clinical candidates for treating Gram-positive infections through TMK.
The total synthesis of racemic rishirilide B has been accomplished. The synthesis serves to define the relative relationships of its stereogenic centers. Also, starting with readily available chiral ...pool, ent‐rishirilide B was synthesized, thereby demonstrating that natural configuration of rishirilide B. The defining step in our total synthesis is the facile cycloreversion of the bis(siloxy)benzocyclobutane and the intermolecular o‐quinodimethide Diels–Alder cycloaddition. We believe that the tight regiochemical guidance in this step arises from a meshing of the electron‐donating effects of the symmetry‐perturbing aromatic OTBS group of the o‐quinodimethide diene with the reactivity differential of the dienophile (enedione), modulated by the hydroxyl group at the α‐position. The validity of the hypothesis of hydroxy‐directed activation of its vicinal ketone function in the context of the enedione dienophile warrants further study. This type of activation may find broader applications in distinguishing reactivity profiles of key closely related functional groups in organic substrates.
Rishirilides are of interest in that they present merged aromatic and alicyclic domains. The total synthesis of racemic rishirilide B has been accomplished (see scheme). The synthesis serves to define the relative relationships of its stereogenic centers. Also, starting with readily available chiral pool, ent‐rishirilide B was synthesized, thereby demonstrating that natural configuration of rishirilide B.
Conrotatory thermal fragmentation of trans-1,2-disilyloxybenzocyclobutenes generates o-quinone dimethides at remarkably low temperatures. Smooth stereoselective Diels−Alder cycloaddition with a range ...of dienophiles provides hydronaphthalene derivatives in excellent yield. Direct oxidative desilylation of the adducts affords the corresponding naphthoquinones. Substitution of the benzene nucleus with an electron-releasing methoxyl group directs the cycloaddition to give good control of regioselectivity in the expected direction. A short synthesis of the aglycon of the anticancer antibiotic idarubicin is presented.
SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in ...the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein–ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro4.5decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.
Because of the complexity derived from the existence of various phosphoinositide 3-kinase (PI3K) isoforms and their differential roles in cancers, development of PI3K inhibitors with differential ...pharmacologic and pharmacokinetic profiles would allow best exploration in different indications, combinations, and dosing regimens. Here, we report BAY 80-6946, a highly selective and potent pan-class I PI3K inhibitor with sub-nanomolar IC50s against PI3Kα and PI3Kδ. BAY 80-6946 exhibited preferential inhibition (about 10-fold) of AKT phosphorylation by PI3Kα compared with PI3Kβ in cells. BAY 80-6946 showed superior antitumor activity (>40-fold) in PIK3CA mutant and/or HER2 overexpression as compared with HER2-negative and wild-type PIK3CA breast cancer cell lines. In addition, BAY 80-6946 revealed potent activity to induce apoptosis in a subset of tumor cells with aberrant activation of PI3K as a single agent. In vivo, single intravenous administration of BAY 80-6946 exhibited higher exposure and prolonged inhibition of pAKT levels in tumors versus plasma. BAY 80-6946 is efficacious in tumors with activated PI3K when dosed either continuously or intermittently. Thus, BAY 80-6946 induced 100% complete tumor regression when dosed as a single agent every second day in rats bearing HER2-amplified and PIK3CA-mutated KPL4 breast tumors. In combination with paclitaxel, weekly dosing of BAY 80-6946 is sufficient to reach sustained response in all animals bearing patient-derived non-small cell lung cancer xenografts, despite a short plasma elimination half-life (1 hour) in mice. Thus, BAY 80-6946 is a promising agent with differential pharmacologic and pharmacokinetic properties for the treatment of PI3K-dependent human tumors.
Theoretical studies of stereoselectivity have been carried out with B3LYP and MP2 calculations. The high endo selectivity of hetero‐Diels–Alder reactions of ortho‐xylylenes with acetaldehydes is ...shown to result from attractive CH–π interactions between alkyl groups of the aldehyde and the aromatic ring in the transition states of the reaction. For the hetero‐Diels–Alder reactions of ortho‐xylylenes with benzaldehyde, the stereoselectivity is shown to be mainly governed by the attractive π–π interactions between the phenyl rings of the benzaldehyde and the ortho‐xylylene. MP2 calculations are necessary to reproduce the stabilizing dispersion interactions.
B3LYP and MP2 calculations show that the high endo selectivities of hetero‐Diels–Alder reactions of ortho‐xylylenes with substituted aldehydes are a result of CH–π or attractive π–π interactions between the aldehyde substituent and the ortho‐xylylene π system (see picture).
Abstract
The BRG/Brahma-associated factors (BAF) family of chromatin remodeling complexes (also referred to as the mSWI/SNF complex) regulates the chromatin landscape of the genome. Through its ...ATP-dependent chromatin remodeling activity, BAF regulates the accessibility of gene-control elements, allowing for the binding of transcription factors. Thus, BAF is a major regulator of lineage- and disease-specific transcriptional programs. We have discovered and developed a novel series of compounds that potently and selectively inhibits the ATPase components of the BAF complex, SMARCA4 and SMARCA2 (also called BRG1 and BRM, respectively). Mutational, structural, and biochemical studies demonstrated that these SMARCA4/SMARCA2 inhibitors act through a unique allosteric mechanism. Pharmacologic inhibition of the BAF complex resulted in lineage-specific changes in chromatin accessibility in cancer cell lines from diverse origins. Phenotypic screening of cancer cell lines showed that uveal melanoma and hematological cancer cell lines were exquisitely sensitive to BAF inhibition. In the example of uveal melanoma, BAF inhibition resulted in the loss of accessibility at the binding sites of the SOX10 and MITF transcription factors, two essential proteins in supporting the proliferation and survival of uveal melanoma cells. Enhancer occupancy of SOX10 and MITF was reduced upon BAF inhibition, and subsequently, the melanocytic and pigmentation gene expression program regulated by these master transcription factors was suppressed. Finally, in a mouse xenograft model of uveal melanoma, BAF inhibition was well tolerated and resulted in dose-dependent tumor regression that correlated with pharmacodynamic modulation of BAF-target gene expression. These data provide the foundation for first-in-human studies of BAF ATPase inhibition as a novel therapeutic to treat uveal melanoma.
Citation Format: Richard C. Centore, Luis M. Soares, Rishi G. Vaswani, Kana Ichikawa, Zhifang Li, Hong Fan, Jeremy Setser, David L. Lahr, Laura Zawadzke, Xueying Chen, Kimberly D. Barnash, Jordana Muwanguzi, Neville Anthony, Gabriel J. Sandoval, Katharine Feldman, Ammar Adam, David Huang, Shawn Schiller, Kevin Wilson, Johannes Voigt, Martin Hentemann, David S. Millan, Ho Man Chan, Steven F. Bellon, Carl P. Decicco, Lan Xu. Discovery of novel BAF inhibitors for the treatment of transcription factor-driven cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1224.
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