Glutaminyl-peptide cyclotransferase-like protein (QPCTL) Inhibitor: Novel cancer immunotherapy for COLD tumors (IND-Filing)
Assays Completed
Co-development with Fosun
In vivo anti-tumor efficacy studies
Combo study with Rituximab, anti-PD-1, or paclitaxel, Azacytidine
In vivo efficacy studies with single agent
In vivo PK-PD
In vivo PK studies
In vivo acute efficacy studies
In vitro ADMET studies
In vitro cell-based
Toxicology studies
Target Rationale
The development of cancer immunotherapies, especially immune checkpoint inhibitors, have shown a new way to treat cancer. However, despite being the most successful cancer immunotherapy so far, majority of patients show primary or acquired resistance to these approaches, since cancer cells can develop various mechanisms to evade tumor-specific and non-specific attacks. Innate immune checkpoints, which interfere with the detection and clearance of malignant cells and suppress innate immune sensing are demonstrated to play key roles in tumor-mediated immune escape.

Glutaminyl-peptide cyclotransferase-like protein (QPCTL) as a novel cancer immunotherapy is responsible for pyroglutamate modification of CD47 N-terminal as well as the N-terminus of chemokine ligand proteins, e.g., CCL2, CCL7, CX3CL1. The modifications on these substrate proteins are all necessary for sustaining the relative signaling activities.

Inhibition of QPCTL can promote immune-mediated tumor killing via blockade of CD47/SIRPα axis and reshaping the tumor immune microenvironment through modulating suppressive myeloid cells toward phagocytic macrophages-enriched landscape, further favors anti-tumor immunity induced by T cell activation.
QPCTL inhibition reprograms tumor myeloid landscape toward anti-tumorigenic profile
Nature Immunology, 2022, 23, 481–482

Insilico Medicine QPCTL Inhibitor Summary – IND-Filing
Novel structure generated by AI
  • Distinctly different structure generated by Insilico Medicine's AI small molecule generation platform Chemistry42
Effective Cancer Immuno-therapy
  • Potent inhibitory activity of SIRP-α binding to CD47-expressing cancer cells
  • Novel I/O class utilizing innate immunity and further boosting adaptive immunity through reprogramming tumor myeloid landscape toward anti-tumorigenic profile
  • Potential broad indications including both NHL/AML and solid tumor
Promising drug-ability as an oral agent
  • Good in vitro ADME profiles
  • Promising PK profiles across different preclinical animal species
Favorable safety margin
  • Promising MOS in rat and dog based on GLP studies without obvious off-target toxicity
  • Clean on Safety Pharmacology

The detection and clearance of cancer cells via phagocytosis induced by innate immune checkpoints plays a significant role in tumor-mediated immune escape. The CD47-SIRPα axis, whose signaling is sustained by QPCTL, is the most well-described innate immune checkpoint which allows the CD47-expressing cancer cells to evade innate immune cell-mediated phagocytosis. The agents that block the CD47–SIRPα interaction are currently being evaluated in multiple ongoing trials, most in combination with pro-phagocytosis agents, e.g. therapeutic antibodies, chemotherapy in patients with leukemia, lymphoma and advanced solid tumors (head and neck squamous cell carcinoma, gastric cancer, breast cancer, colorectal cancer, etc.). The QPCTL inhibitor could be developed for the patients with these indications, especially when they are resistant to the standard-of-care therapies, e.g. azacytidine, rituximab, paclitaxel, trastuzumab, cetuximab, etc.

Project Status – IND-Filing
PandaOmics-powered target ID and Chemistry42 facilitated compound generation enabling quick progression towards the PCC stage and nominating an Insilico Medicine's compound as a cancer immunotherapy targeting QPCTL. In vitro and vivo data showed that the compound exhibited potent anti-tumor activity by blocking the CD47/SIRPα signaling axis and inhibiting the MCPs/CCR2 signaling pathway. Several in vivo anti-tumor efficacy studies in human cancer xenograft and mouse syngeneic models showed strong anti-tumor activity when combined with different SOC (standard of care) therapies. We expect to file an IND application in 2023.