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Chemical Biology Lecture: Discovery of the Phase I Clinical Agent and MPS1 inhibitor BOS172722 for the Treatment of Triple Negative Breast Cancer

Thursday 9 May 2019
Gorlaeus Building
Einsteinweg 55
2333 CC Leiden


Dr. Swen Hoelder leads the Medicinal Chemistry 4 team within the Cancer Research UK Cancer Therapeutics Unit, a part of the Division of Cancer Therapeutics, at The Institute of Cancer Research, London. In November 2017 he was awarded a readership (UK analogue of a full professor without chair) in Medicinal Chemistry and Drug Design.

Medicinal chemistry plays a crucial role towards the generation of a new drug. Drug candidates are identified through creative design, chemical synthesis and systematic testing of chemical compounds. These drug candidates are then progressed to clinical trials. Dr. Hoelder and his team apply their medicinal chemistry skills to discover novel cancer drugs in collaboration with other research teams both within the ICR and externally. A recent example is the discovery of a series of pyrimidopyridine inhibitors for the cancer target MPS1 and the chemical optimization of this series to yield the clinical candidate BOS172722. BOS172722 is currently undergoing Phase 1 clinical development for triple negative breast cancer.

Dr. Hoelder studied chemistry at the University of Muenster (Germany). He completed his PhD in organic chemistry at the Technical University in Berlin in the team of Professor S. Blechert. Following his PhD, Dr Hoelder spent two years in the lab of Professor P.G. Schultz at the University of California, Berkeley establishing methods to identify novel enzymes through selection from large protein libraries. His Post-Doctoral research was supported by a Feodor Lynen Fellowship from the Alexander von Humboldt Foundation.

Dr. Hoelder then joined the department of Medicinal Chemistry at Hoechst Marion Roussel (now Sanofi), a major pharmaceutical company, where he predominately worked on diabetes therapies. In addition, he led teams that were responsible for the creation of a kinase screening library and explored the application of Bio-NMR for kinase drug discovery in collaboration with the group of Professor H. Schwalbe at Frankfurt University. In 2005, he joined Altana (now Takeda) to work on cancer therapies, where he led a team of chemists that discovered two pre-clinical candidates.

In October 2007, Dr. Hoelder joined the faculty of the ICR and is now applying his medicinal chemistry experience to discover novel drugs in the unique and collaborative environment of the ICR.

In 2017, he was awarded a readership in Medicinal Chemistry and Drug Design and in 2018 took up the role as a senior tutor at the ICR.


MPS1 (also known as TTK), is a dual-specificity protein kinase and one of the main components of the spindle assembly checkpoint. Cancer cells heavily rely on MPS1 to cope with aneuploidy resulting from aberrant numbers of chromosomes and MPS1 has been found to be upregulated in a large number of tumour types making MPS1 an attractive cancer target.

The talk will focus on different aspects of our MPS1 drug discovery project. The first aspect is the discovery of BOS172722, our clinical candidate currently undergoing Phase I clinical trials. The medicinal chemistry effort started with an azaindole screening hit. Structure based optimisation led to compounds with greatly improved potency and selectivity exemplified by the chemical probe CCT251455.

In addition, using knowledge based design we discovered a second class of MPS1 inhibitors, the pyridopyrimidines. Medicinal chemistry optimisation of this class ultimately yielded BOS172722. BOS172722 shows excellent potency, kinase selectivity, and ADME properties. We will describe key medicinal chemistry challenges on route to the drug, particularly optimisation of metabolic stability.

The second part of the talk will be focused on our efforts to identify patient populations that benefit from treatment with MPS1 inhibitors. Owing to a narrow therapeutic window in preclinical models, the progression of MPS1 inhibitors required the identification of tumour types and clinical contexts that are particularly sensitive to MPS1 inhibition. Our work to identify patient populations will be described, leading to clinical hypotheses that are underpinned by in vivo data and that we are testing in clinical trials in clinical trials.

Finally, the synthetic chemistry developed to prepare key compounds and to upscale the clinical candidate will be described.

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