First-in Class Drug Targeting DDT2 (Code Name) Transcription Factor for Primary Cancers
We introduce the process of finding key targets for primary cancers using our AI technologies such as Wx and DearTRANS.
Introduction
Cancer is a leading cause of death worldwide and therefore much effort is being made to treat it. Nevertheless, the main causes of cancer are not clear, and most cancer patients die of relapse after a series of treatments. Although recent advances in treatment strategies for patients with specific mutations (EGFR, KRAS, etc.) so-called ‘precision medicine’ have increased their overall survival or disease-free survival with the mutations, only a few cancer patientsshow complete remission with these treatments.
Method & Result
The DDT2 (code name) transcription factor, which was identified as a novel target for various primary cancers using WX and DearTRANS, our AI-powered target discovery algorithms, is overexpressed in most cancer tissues(Figure 1) compared to adjacent normal tissues (Figure 2). Therefore, it is a promising target likely having properties with low toxicity for normal cells but high efficacy for cancer cells.
[Figure 1] Comparative analysis of expression patterns of DDT2 genes in cancer tissues (T) and adjacent normal tissues (N)
[Figure 2] Expression pattern of DDT2 gene in normal tissues
In addition, our meta-analysis revealed that the DDT2 transcription factor regulates key genes associated with cell cycle pathways such as CENPF (centromere protein F), etc. by binding directly to their promoter regions (Figure 3).
[Figure 3] DDT2 transcription factors (peaks) that bind to the CENPF gene promoter region
Furthermore, we confirmed that the expression level of the DDT2 gene is significantly associated with the prognosis of patients with renal, liver, pancreatic, and lung cancers (Figure 4).
[Figure 4] Prognosis in patients with the overexpression of DDT2 gene (higher expression results in lower overall survival(OS))
Deargen has successfully created a small chemical conjugate (DGD-003) that can selectively eliminate the DDT2 transcription factor in cancer cells and will further modify a compound to lower its toxicity with better ADMET properties using MolEQ (molecular equalizer), Deargen’s state-of-the-art AI-powered lead optimization technology. DGD-003 is based on the emerging cutting-edge approach called PROTAC (proteolysis targeting chimera). Western blot and cell viability assays with DGD-003 in breast cancer cell lines (MCF-7 and SKBR3) showed obvious degradation of target protein DDT2 in a dosage-dependent manner.
We will conduct a series of verification of DGD-003 in lung cancer, liver cancer, and breast cancer cell lines with appropriate animal models and establish a clinical plan for the development of first-in-class drug for primary cancers.