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Research Interests:
The MYC oncogene is causally involved in the pathogenesis of most types of human cancer but it remains therapeutically untargeted. The mTORC1 protein complex regulates cap-dependent translation through 4EBP1 and S6K and thereby,... more
The MYC oncogene is causally involved in the pathogenesis of most types of human cancer but it remains therapeutically untargeted. The mTORC1 protein complex regulates cap-dependent translation through 4EBP1 and S6K and thereby, downstream MYC protein expression. However, to date, agents such as rapalogs that selectively target mTORC1 (as compared to mTORC2) fail to reactivate 4EBP1 and thus, to block MYC in vivo. In contrast, agents that nonselectively inhibit both protein complexes of the mTOR pathway, mTORC1 and mTORC2, can activate 4EBP1, but often suffer from a lack of tolerability including in vivo hepatotoxicity and immunosuppression. Here, we report the anti-tumor activity of bi-steric mTORC1-selective inhibitors, including Revolution Medicines clinical candidate RMC-5552, that potently and selectively target mTORC1 over mTORC2. In an autochthonous transgenic mouse model of MYC-amplified and MYC-driven hepatocellular carcinoma (HCC), representative bi-steric mTORC1-selective...
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Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAF-driven cancers, effective targeted therapies are lacking for most cancers... more
Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAF-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRAS). SHP2 inhibitor treatment decreases oncogenic RAS/RAF/MEK/ERK signalling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS/MAPK pathway activation in cancers with RAS-GTP-dependent oncogenic BRAF, NF1 loss and n...
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M. tuberculosis thymidylate kinase (Mtb TMK) has been shown in vitro to be an essential enzyme in DNA synthesis. In order to identify novel leads for Mtb TMK, we performed a high throughput biochemical screen and an NMR based fragment... more
M. tuberculosis thymidylate kinase (Mtb TMK) has been shown in vitro to be an essential enzyme in DNA synthesis. In order to identify novel leads for Mtb TMK, we performed a high throughput biochemical screen and an NMR based fragment screen through which we discovered two novel classes of inhibitors, 3-cyanopyridones and 1,6-naphthyridin-2-ones, respectively. We describe three cyanopyridone subseries that arose during our hit to lead campaign, along with cocrystal structures of representatives with Mtb TMK. Structure aided optimization of the cyanopyridones led to single digit nanomolar inhibitors of Mtb TMK. Fragment based lead generation, augmented by crystal structures and the SAR from the cyanopyridones, enabled us to drive the potency of our 1,6-naphthyridin-2-one fragment hit from 500 μM to 200 nM while simultaneously improving the ligand efficiency. Cyanopyridone derivatives containing sulfoxides and sulfones showed cellular activity against M. tuberculosis. To the best of our knowledge, these compounds are the first reports of non-thymidine-like inhibitors of Mtb TMK.
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The protein kinase superfamily represents both an enormous opportunity and a unique challenge for drug discovery. Protein kinases play central roles in the cellular economy and it is well known that a large number of diseases involve... more
The protein kinase superfamily represents both an enormous opportunity and a unique challenge for drug discovery. Protein kinases play central roles in the cellular economy and it is well known that a large number of diseases involve aberrant protein kinase activity. This review discusses how fragment based screening strategies, such as virtual screening, NMR and high-throughput X-ray crystallography are being employed to identify new chemo-types to produce the next generation of protein kinase inhibitors.
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We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyloxypyridine 1 (IC 50 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 (IC 50 35 μM) identified using X-ray crystallographic screening of p38α MAP kinase.... more
We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyloxypyridine 1 (IC 50 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 (IC 50 35 μM) identified using X-ray crystallographic screening of p38α MAP kinase. Using two separate case studies, the article focuses on ...
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Page 2256. The authors have been notified by Plexxikon that the structure of PLX4032, published in Expert Opin. Ther. Targets 2007, 11, (12)) 1587−1609 (Figure 4) and presented in p 2256, Figure 1, was incorrect and the correct one has... more
Page 2256. The authors have been notified by Plexxikon that the structure of PLX4032, published in Expert Opin. Ther. Targets 2007, 11, (12)) 1587−1609 (Figure 4) and presented in p 2256, Figure 1, was incorrect and the correct one has not been released.
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Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have... more
Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC(50) approximately 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.
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Doing the right things or doing things right: what is the most important focus for current drug discovery to secure delivery of new drugs of sustainable value to patients, healthcare professionals and healthcare providers? Some of the... more
Doing the right things or doing things right: what is the most important focus for current drug discovery to secure delivery of new drugs of sustainable value to patients, healthcare professionals and healthcare providers? Some of the challenges faced today in drug discovery are addressed here: the relationship between R&D speed, cost and quality; how selection of performance metrics can affect the quality of the R&D output; the importance of leadership and management; how process orientation can affect, for example, creativity and innovation; the importance of selecting the right pharmacologic target and the right chemical lead; and why the use of drug-target kinetic and thermodynamic data to drive lead selection and lead optimization could increase success rates.
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The kinetics of ligand-target interactions have been recognised as being instrumental in dictating the efficacy of drug action. Increased focus on kinetic signatures in drug discovery has concincided with improvements in label free... more
The kinetics of ligand-target interactions have been recognised as being instrumental in dictating the efficacy of drug action. Increased focus on kinetic signatures in drug discovery has concincided with improvements in label free methodology for measuring kinetic parameters. Simultaneously, focus has also been applied to increasing the quality of compounds, in terms of their physicochemical properties. To facilitate this drive towards higher compound quality, metrics such as ligand efficiency and enthalpic efficiency have been employed. We propose another metric, kinetic efficiency, that may be used pragmatically to help identify those compounds displaying differentiated kinetic behaviour. The combination of these metrics has the potential to improve decision-making in drug discovery leading to higher quality compounds and series.
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A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our early efforts at optimization of the quinoline core, the... more
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.
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A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our efforts at further optimization of this series, culminating... more
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.
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11β-HSD1 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. In this program of work we describe how a series of neutral 2-thioalkyl-pyridine 11β-HSD1 inhibitors... more
11β-HSD1 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. In this program of work we describe how a series of neutral 2-thioalkyl-pyridine 11β-HSD1 inhibitors were optimized in terms of their pharmacokinetic properties to give compounds with excellent bioavailability in both rat and dog through a core change to pyrimidine. A potential reactive metabolite issue with 4-thioalkyl-pyrimidines was circumvented by a switch from sulfur to carbon substitution.
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Following a heart attack, more than a billion cardiac muscle cells (cardiomyocytes) can be killed, leading to heart failure and sudden death. Much research in this area is now focused on the regeneration of heart tissue through... more
Following a heart attack, more than a billion cardiac muscle cells (cardiomyocytes) can be killed, leading to heart failure and sudden death. Much research in this area is now focused on the regeneration of heart tissue through differentiation of stem cells, proliferation of existing cardiomyocytes and cardiac progenitor cells, and reprogramming of fibroblasts into cardiomyocytes. Different chemical modalities (i.e. methods or agents), ranging from small molecules and RNA approaches (including both microRNA and anti-microRNA) to modified peptides and proteins, are showing potential to meet this medical need. In this Review, we outline the recent advances in these areas and describe both the modality and progress, including novel screening strategies to identify hits, and the upcoming challenges and opportunities to develop these hits into pharmaceuticals, at which chemistry plays a key role.