PMS2 Programme

 

Discovery of potent and selective chemical tool NP1867, structurally matched inactive control NP2567, and selective PMS2 degrading PROTAC chemical tools, enabled validation of PMS2 as a druggable and functionally relevant target in the MMR pathway. In cell-based assays in both murine and human cell lines, we demonstrated that NP1867, but not inactive control NP2567, elicits the classic hallmarks of MMR-deficiency (e.g. 6-thioguanine (6-TG) tolerance and temozolomide (TMZ) resistance​). Long-term inhibition of PMS2 in murine and human cancer cell lines with NP1867 led to a classical MMR-d genotype - increased TMB, enriched MMR-d mutational fingerprints, and MSI-High (MSI-H) status. These genotypic changes can be accelerated in combination with standard-of-care treatments; for example, platin-based chemotherapies. Inoculation of syngeneic immunocompetent mice with murine cancer cells pretreated with NP1867 led to CPI sensitivity, tumour growth delay, and complete responses (Figures 3 and 4).

In July 2025, we nominated an orally bioavailable preclinical development candidate, NP3452, that phenocopies and genocopies findings with our tool NP1867. Importantly, NP3452 is non-cytotoxic and does not ameliorate or exacerbate the cytotoxicity of standard-of-care agents in preclinical studies in human cancer cell lines. Preclinical toxicology studies are ongoing with CTA filing anticipated by Q4 2026 to enable first-in-human studies in 1H 2027.

For further insights, please see the posters Â鶹´«Ã½ presented at EORTC (2023) and AACR (2024).

 

Figure 3

 
Figure 3

Treatment of murine CT26 cells with NP1867 leads to genotypic changes associated with MMR deficiency

Murine CT26 cells were treated for up to 10 cycles (T10) of 4-weeks with DMSO (vehicle control) or NP1867 at 0.5 µM in triplicate. Analysis of 4 (T4), 6 (T6), 8 (T8) and 10 (T10) cycles of 4-weeks treatment, compared to the start of the experiment: A Tumour mutational burden (TMB) (SNVs + Indels) expressed as the number of mutations gained/Mb; B MSI-Score analysis, dotted line depicts the threshold for MSI-H status; C Number of unique mutations gained per replicate and per treatment group (DMSO or NP1867) at each time point. A and B, data shown as box-and-whisker plots, median IQR minimum and maximum; C data shown as mean ± s.e.m. A-C, Statistical analysis: two-tailed t-test. ns = not significant, *P<0.05, **P<0.01, ***P<0.001.

Figure 3

Figure 4

 
Figure 4

Chronic pre-treatment with NP1867 sensitises murine CT26 tumours to anti-PD-1 therapy in vivo

Murine CT26 cells were treated with NP1867 at 0.5 µM or DMSO in vitro for 10 cycles of 4-weeks (T10). A and B, Tumour growth curves (n = 20 mice / group) of NP1867-treated (A) and DMSO-treated (B) CT26 T10 cells in immunocompetent BALB/c mice, in the presence of isotype control or anti-PD-1 therapy. Dotted lines denote isotype control or anti-PD-1 treatments. C, Tumour growth in immunocompromised NOD.SCID mice. n = 8 mice / group. In all panels, tumour volume shown as mean ± s.e.m. until 75% of animals per group remained in study. Statistical test: nonparametric Mann-Whitney test. ns = not significant, *P<0.05, **P<0.01, ***P<0.001​.

Figure 4