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 RAS–ERK 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 RAS–ERK 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.
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.
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.
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.
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.
A synthesis of (−)‐10‐hydroxyacutuminine is reported. The strategy features an intramolecular, photochemical 2+2 cycloaddition to build the propellane core followed by a retro‐aldol/Dieckmann sequence to form the requisite spirocyclic cyclopentenone.
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.
A synthesis of (−)‐10‐hydroxyacutuminine is reported. The strategy features an intramolecular, photochemical 2+2 cycloaddition to build the propellane core followed by a retro‐aldol/Dieckmann sequence to form the requisite spirocyclic cyclopentenone.
The acutumine alkaloids are a family of architecturally complex propellane natural products with promising medicinal properties. Herein, we disclose the continued development of a synthetic strategy ...toward the asymmetric total synthesis of acutumine alkaloids. The spirocyclic scaffold was synthesized in two new series, which follow our successful access to the dechloroacutumine core in 2013. Central to the synthetic design is the retro-aldol/Dieckmann cyclization of a cyclobutyl lactone to install the spirocycle. The key cyclobutane intermediate is obtained via a photo-mediated 2+2-cycloaddition of a furanyl dihydroindolone, which is accessible via a stereoselective 1,2-addition/reductive cyclization sequence of a benzoquinone-derived imine. Installation of the dimethoxyenone motif is accomplished via a late-stage elimination of a dimethoxyketal, which furnished the requisite vinylogous ester after methylation. Overall, these efforts have culminated in the synthesis of the complete carbocyclic core and oxidation pattern of the natural product (–)-acutuminine, with a C10 neopentyl alcohol in place of the neopentyl chloride.Ten of the known acutumine alkaloids contain a neopentyl chloride; this motif provided underlying motivation for the development of novel radical deoxychlorination reactions, including the chlorination of cesium oxalates. This reaction allows access to hindered 2° and 3° alkyl chlorides, provides complementary reactivity to standard heterolytic conditions, and is performed under mild conditions using visible light and ethyl trichloroacetate as a Cl• source. Application to deoxybromination and deoxyfluorination is also demonstrated, showcasing the versatility of the discovered halogenation. This method should find broad utility in the deoxyhalogenation of hindered alcohols, particularly in the pharmaceutical industry where selective installation of fluorides is a common challenge.
The acutumine alkaloids are a family of architecturally complex propellane natural products with promising medicinal properties. Herein, we disclose the continued development of a synthetic strategy ...toward the asymmetric total synthesis of acutumine alkaloids. The spirocyclic scaffold was synthesized in two new series, which follow our successful access to the dechloroacutumine core in 2013. Central to the synthetic design is the retro-aldol/Dieckmann cyclization of a cyclobutyl lactone to install the spirocycle. The key cyclobutane intermediate is obtained via a photo-mediated 2+2-cycloaddition of a furanyl dihydroindolone, which is accessible via a stereoselective 1,2-addition/reductive cyclization sequence of a benzoquinone-derived imine. Installation of the dimethoxyenone motif is accomplished via a late-stage elimination of a dimethoxyketal, which furnished the requisite vinylogous ester after methylation. Overall, these efforts have culminated in the synthesis of the complete carbocyclic core and oxidation pattern of the natural product (–)-acutuminine, with a C10 neopentyl alcohol in place of the neopentyl chloride.
Ten of the known acutumine alkaloids contain a neopentyl chloride; this motif provided underlying motivation for the development of novel radical deoxychlorination reactions, including the chlorination of cesium oxalates. This reaction allows access to hindered 2° and 3° alkyl chlorides, provides complementary reactivity to standard heterolytic conditions, and is performed under mild conditions using visible light and ethyl trichloroacetate as a Cl• source. Application to deoxybromination and deoxyfluorination is also demonstrated, showcasing the versatility of the discovered halogenation. This method should find broad utility in the deoxyhalogenation of hindered alcohols, particularly in the pharmaceutical industry where selective installation of fluorides is a common challenge.
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