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
Jahnke et al., “Fragment-to-Lead Medicinal Chemistry Publications in 2019”; Journal of Medicinal Chemistry, 2020
Tolinapant (ASTX660) is a potent, non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP) , which is currently being tested in a first in human phase I-II clinical trial in patients with advanced solid tumours and lymphomas (NCT02503423) . 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.
- G Ward et al., 2018, Mol Cancer Therapeutics Jul;17(7):1381-1391
- A Hollebecque et al., 2019, AACR-NCI-EORTC International Conference on Molecular
Targets and Cancer Therapeutics
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.
MAPK signalling is frequently dysregulated in cancer. The pathway can Panel composition and the number of responding cell lines Examples of dose-response curves Anti-tumor activity of SHP2i, ASTX029 and combination in MIA PaCa-2 xenograft be targeted by inhibition of different nodes and is tightly regulated by feedback mechanisms. Resistance to single-agent therapies frequently occurs through several different mechanisms including upregulation of receptor tyrosine kinases (RTKs), therefore, combination therapies are of interest.
The Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) is a key regulator of MAPK pathway downstream of RTKs and upstream of RAS, whilst ERK acts at the bottom of the pathway phosphorylating multiple substrates.
We investigated the potential of targeting the MAPK pathway through a combination of SHP2 and ERK inhibition in preclinical models. Using a SHP2 inhibitor (SHP2i) discovered by our structure-based drug discovery programme and ASTX029, an ERK inhibitor in a Phase I-II clinical trial (NCT03520075), we tested panels of cell lines representing various indications and genetic backgrounds in vitro and confirmed enhanced tumor growth inhibition by the combination in a xenograft model.
- The MAPK signaling pathway is commonly upregulated in human cancers due to oncogenic mutations of upstream
components such as BRAF or KRAS.
- MAPK pathway inhibition has been clinically validated by BRAF and MEK inhibitors.
- As the final node in the MAPK pathway, ERK is an attractive therapeutic target for the treatment of MAPK-activated cancers, including those resistant to upstream inhibition.
- Previously we described the fragment-based discovery of a chemical series targeting ERK. Here we disclose for the first time the structure of the clinical candidate, ASTX029.
- Heightman et al., (2018). J Med Chem 61; 4978
Cadilla et al., “The exploration of aza-quinolines as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors with low brain exposure”; Bioorganic & Medicinal Chemistry, 2020
Downes et al., “Design and Synthesis of 56 Shape-Diverse 3D Fragments”; Chemistry: A European Journal, 2020