ABSTRACT
An enantioselective synthesis of (-)-10-hydroxyacutuminine is reported. Central to our strategy is a photochemical [2+2] cycloaddition that forges two of the quaternary stereocenters present in the acutumine alkaloids. A subsequent retro-aldol/Dieckmann sequence furnishes the spirocyclic cyclopentenone. Efforts to chlorinate the acutumine scaffold at C10 under heterolytic or radical deoxychlorination conditions led to the synthesis of an unexpected cyclopropane-containing pentacycle.
Subject(s)
Cyclization , Cycloaddition Reaction , StereoisomerismABSTRACT
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-azaspiro[4.5]decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Neoplasms/enzymology , Protein Tyrosine Phosphatase, Non-Receptor Type 11/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism , Allosteric Regulation/drug effects , Allosteric Regulation/physiology , Animals , Antineoplastic Agents/therapeutic use , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Humans , Macaca fascicularis , Mice , Neoplasms/drug therapy , Neoplasms/pathology , Rats , Tumor Cells, Cultured , Xenograft Model Antitumor Assays/methodsABSTRACT
A radical deoxychlorination of cesium oxalates has been developed for the preparation of hindered secondary and tertiary alkyl chlorides. The reaction tolerates a number of functional groups, including ketones, alcohols, and amides, and provides complementary reactivity to standard deoxychlorination reactions proceeding by heterolytic mechanisms. Preliminary studies demonstrate that the developed conditions can also be applied to deoxybromination and deoxyfluorination reactions.
ABSTRACT
The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RASERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 µM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RASERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.
Subject(s)
Neoplasms/drug therapy , Neoplasms/enzymology , Piperidines/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 11/antagonists & inhibitors , Pyrimidines/pharmacology , Receptor Protein-Tyrosine Kinases/metabolism , Allosteric Regulation/drug effects , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Humans , Inhibitory Concentration 50 , MAP Kinase Signaling System/drug effects , Mice , Mice, Nude , Models, Molecular , Neoplasms/pathology , Oncogene Protein p21(ras)/metabolism , Piperidines/chemistry , Piperidines/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Stability/drug effects , Protein Structure, Tertiary/drug effects , Protein Tyrosine Phosphatase, Non-Receptor Type 11/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Reproducibility of Results , Xenograft Model Antitumor AssaysABSTRACT
SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.