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Poon et al., “The role of SQSTM1 (p62) in mitochondrial function and clearance in human cortical neurons”; Stem Cell Reports 2021

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Poon et al., “The role of SQSTM1 (p62) in mitochondrial function and clearance in human cortical neurons”; Stem Cell Reports 2021

https://doi.org/10.1016/j.stemcr.2021.03.030

Chessari at al. Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein–Protein Interaction; Med Chem 2021

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Chessari at al., “Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein–Protein Interaction”; Med Chem 2021

https://doi.org/10.1021/acs.jmedchem.0c02188

Sethi et al., “Leveraging omic features with F3UTER enables identification of unannotated 3’UTRs for synaptic genes”

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Sethi et al., “Leveraging omic features with F3UTER enables identification of unannotated 3’UTRs for synaptic genes”

https://www.nature.com/articles/s41467-022-30017-z

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Brain et al., “The Discovery of Kisqali® (Ribociclib): A CDK4/6 Inhibitor for the Treatment of HR+/HER2− Advanced Breast Cancer”; Successful Drug Discovery; Vol 5; 2021; chapter 9

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Brain et al., “The Discovery of Kisqali® (Ribociclib): A CDK4/6 Inhibitor for the Treatment of HR+/HER2− Advanced Breast Cancer”; Successful Drug Discovery; Vol 5; 2021; chapter 9

https://doi.org/10.1002/9783527826872.ch9

Grainger et al., “A Perspective on the Analytical Challenges Encountered in High-Throughput Experimentation”; Organic Process Research and Development, 2021

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Grainger et al., “A Perspective on the Analytical Challenges Encountered in High-Throughput Experimentation”; Organic Process Research and Development, 2021

https://dx.doi.org/10.1021/acs.oprd.0c00463

St. Denis et al., “Fragment-based drug discovery: opportunities for organic synthesis”; RSC Medicinal Chemistry, 2021

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St. Denis et al., “Fragment-based drug discovery: opportunities for organic synthesis”; RSC Medicinal Chemistry, 2021

https://pubs.rsc.org/en/content/articlelanding/2021/md/d0md00375a#!divAbstract

Holvey et al., “Identifying and Developing Small Molecule Inhibitors of Protein–Protein Interactions”; RSC Publications, 2020

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Holvey et al., “Identifying and Developing Small Molecule Inhibitors of Protein–Protein Interactions”; RSC Publications, 2020

https://doi.org/10.1039/9781839160677

Jahnke et al., “Fragment-to-Lead Medicinal Chemistry Publications in 2019”; Journal of Medicinal Chemistry, 2020

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Jahnke et al., “Fragment-to-Lead Medicinal Chemistry Publications in 2019”; Journal of Medicinal Chemistry, 2020

https://doi.org/10.1021/acs.jmedchem.0c01608

2020 EORTC-NCI-AACR: The non-peptidomimetic cIAP1/2 and XIAP antagonist tolinapant promotes an anti-tumour immune response in T-cell lymphoma

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The non-peptidomimetic cIAP1/2 and XIAP antagonist tolinapant promotes an anti-tumour immune response in T-cell lymphoma

Summary

Tolinapant (ASTX660) is a potent, non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP) [1], which is currently being tested in a first in human phase I-II clinical trial in patients with advanced solid tumours and lymphomas (NCT02503423) [2]. IAP antagonists have been reported to exhibit broad immuno-modulatory effects on both the innate and adaptive immune systems. We have investigated the profile of tolinapant in preclinical T cell lymphoma models and evaluated tolinapant’s ability to enhance immune mediated killing of T cell lymphoma cells, both in vitro and in vivo.

References:

  1. G Ward et al., 2018, Mol Cancer Therapeutics Jul;17(7):1381-1391
  2. A Hollebecque et al., 2019, AACR-NCI-EORTC International Conference on Molecular
    Targets and Cancer Therapeutics

Identification of potent small molecule allosteric inhibitors of SHP2

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Identification of potent small molecule allosteric inhibitors of SHP2

Summary
SHP2 is a ubiquitously expressed protein tyrosine phosphatase required for growth factor signalling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes.

Genetic knockdown and pharmacological inhibition of SHP2 inhibits proliferation of RTK-driven cancer cell lines and suppresses RAS/MAPK signalling.

SHP2 inhibitors are a promising therapeutic approach as RTK deregulation often leads to a wide range of cancers and several compounds are being tested in the clinic.

Using our fragment-based screening approach, PyramidTM, we identified fragment hits binding to the tunnel region<sup>1</sup> between the phosphatase domain and the C-SH2 domain of SHP2 which were improved using structure-guided design.

Here we describe the optimisation of mM fragment hits into potent SHP2 antagonists with in vitro and in vivo anti-tumour activity.