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Cancer’s Achilles Heel


Step Pharma is a pioneer of CTPS1 inhibition, a new approach with the potential to yield a highly selective, safe and effective cancer treatment for both blood cancers and solid tumours.

CTPS1 Role in Lymphocyte Proliferation

Step Pharma has unlocked the de novo pyrimidine synthesis pathway – a challenge which has eluded cancer researchers for years. We have demonstrated that all cancers exhibit a dependency on CTPS1 and that genomic loss of CTPS2 dependency, indicating that Step Pharma’s approach may be used to treat many different types of cancer.

Our novel approach could see the highly selective treatment of cancer without the significant side effects associated with current and emerging cancer therapies.

Driven by our deep understanding of CTPS1 biology and nucleotide synthesis, Step Pharma has discovered dencatistat, a first-in-class, highly selective, orally bioavailable CTPS1 inhibitor. It is a targeted therapy that kills cancer cells while sparing healthy cells

Inhibited CTPS1
Dencatistat is a potent, highly selective, orally bioavailable CTPS1 inhibitor with greater than a 1,000 selectivity for human CTPS1 over CTPS2. Dencatistat binds to each monomer of CTPS1 mimicking CTP and thus inhibits the enzymatic activity of CTPS1.

The de novo pyrimidine synthesis pathway.

The nucleotide cytidine 5′ triphosphate (CTP) is a precursor required for the synthesis of DNA, RNA and phospholipids. CTP originates from two sources: the nucleotide salvage pathway and the de novo nucleotide synthesis pathway. De novo synthesis of CTP is required for DNA replication. The rate limiting step is conversion of UTP to CTP which can be catalyzed by CTP Synthase 1 (CTPS1) or CTPS2.

In 2014 Prof. Alain Fischer and his collaborators at the Imagine Institute identified loss-of-function homozygous CTPS1 mutations in eight children which caused a novel immunodeficiency characterised by impaired capacity of activated lymphocytes to proliferate, without affecting cells outside the blood system (Martin et al., Nature. 2014 Jun 12;510(7504):288-92).

These findings demonstrated that CTPS1 has an essential and non-redundant role in lymphocyte proliferation while CTPS2 allows normal non-blood cells to proliferate independently from CTPS1.

Whilst CTPS2 activity is sufficient for the proliferation of normal cells outside the blood system, our work suggests that all cancer cells have become addicted to CTPS1.

Based upon this ground-breaking research, Step Pharma was founded to convert this human genetic observation into a potential therapy for blood cancers and solid tumours.

The human genetic studies demonstrated that CTPS1 is essential for lymphocyte proliferation and thus inhibition of CTPS1 would be a therapeutic option for malignancies such as leukaemia and lymphoma. Further genetic studies have shown that many solid tumours have deleted CTPS2 also making them exclusively dependent on CTPS1 for pyrimidine synthesis.

CTPS1 in Solid Tumours

Prevalence of CTPS2 loss across different cancer types

CTPS1 in Solid Tumours

CTPS2 loss renders cancer cells dependent on CTPS1 for their survival. Dencatistat is synthetically lethal for cancers with CTPS2 loss.

Driving a step change in the treatment of cancer for patients.

DNA and RNA synthesis are essential metabolic processes to support cell growth and division.
01  I  07
Cancer cells have an increased proliferation rate and nucleotide synthesis is a known therapeutic vulnerability.
02  I  07
Historically drugs targeting inhibition of pyrimidine synthesis (PALA, DHODH, CPEC) have failed primarily due to dose limiting toxicity.
03  I  07
De novo synthesis of cytidine triphosphate (CTP) is required for DNA replication.
04  I  07
The rate limiting step is conversion of UTP to CTP which can be catalyzed by CTP Synthase 1 (CTPS1) and CTPS2.
05  I  07
All cancer cell lines appear addicted to CTPS1 for pyrimidine synthesis whereas CTPS2 is not essential.
06  I  07
This provides a point of differentiation versus previous attempts to block pyrimidine synthesis based upon the relative importance of CTPS1 vs CTPS2 in cancer biology.
07  I  07

3D crystal structure showing dencatistat bound to CTPS1.


Our lead CTPS1 inhibitor dencatistat has the potential to become a key treatment for a multitude of cancers.

Dencatistat is in clinical development for the treatment of blood cancers, with the potential for accelerated approval from a single arm phase 2 study. Dencatistat is also in clinical development for solid tumours with the initial focus on ovarian cancer. In the future dencatistat could also form the backbone of various treatment regimens for solid tumours.

Dencatistat, a pipeline in a product


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Step Pharma
15 rue Louis et Auguste Lumière
Technoparc du Pays-de-Gex
01630 Saint-Genis-Pouilly