CTPS1 Inhibitors

Step Pharma’s most advanced candidate is STP938, a small molecule inhibitor of CTPS1 currently in non-clinical development.

Human genetics has demonstrated that CTPS1 has an essential and non-redundant role in lymphocyte proliferation. CTPS2 has a broad tissue expression profile and is unable to complement for the lack of CTPS1. Patients carrying the CTPS1Δ18 mutation have no phenotype on other tissues.

Selective inhibition of CTPS1 (avoiding CTPS2) thus represents an ideal target for inhibition of T cell proliferation. CTPS1 could be the Achilles heel for T-cell proliferation.

STP938 is a potent, selective inhibitor of CTPS1.

STP938 has shown anti-proliferative and pro-apoptotic effects against a range of T-cell cancer cell lines.

STP938 has demonstrated anti-tumour effect in several animal models of cancer.

STP938 will enter clinical development in 2021 for the treatment of T-cell blood cancers.

STP938 is efficacious in vivo in Jurkat CDx T-cell xenograft model

Oral STP938 dosed 30mg/kg TID every third day regressed the tumour volume by up to 43% over the treatment period. This was superior to vincristine 0.5mg/kg dosed iv day 1 and day 9. Tumour growth is evident once dosing of STP938 is stopped

Publications

CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation

Martin et al., Nature. 2014 Jun 12;510(7504):288-92

Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation.

JCI Insight 2020 Mar 12;(5):e 133880

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