Exploring SPK98 for the Selective Sensitization of ATM- or P53-Deficient Cancer Cells

Abstract

Frequent mutation in the ATM/P53 signaling pathway has been documented in many human cancers. Reportedly, cancer cells with deficient P53/ ATM pathways depend on functional Ataxia-telangiectasia and Rad3-related (ATR) protein for survival. This has prompted research in developing ATR inhibitors for the selective sensitization of cancer cells that are P53/ATM-deficient, but no clinical success has been attained thus far. This study explores the therapeutic potential of SPK98, an analogue of Torin2 in P53-and ATM-deficient cancer cells. Furthermore, the prospect of improving the therapeutic outcome of the genotoxic agent was also explored. SPK98 was shown to inhibit full-length human ATR protein purified from HEK293T cells. Cellular investigation using SPK98 demonstrated that it selectively sensitizes P53-and ATM-deficient cells at low concentrations compared to P53-/ATM-proficient cells. Furthermore, SPK98 drives the cancer cells toward cell death by promoting the formation of DNA double-strand breaks. Taken together, our findings suggest that SPK98 is a promising therapeutic molecule for P53-or ATMdeficient malignancy that merits additional preclinical investigation.

In silico Design, Synthesis and Biological Evaluation of Novel Thieno[3,2‐d]pyrimidine Derivatives for Cancer Therapy – A Preliminary Study on the Inhibitory Potential towards ATR Kinase Domain and PIKK Family

“…The crystal structures of mTOR (PDB ID: 4JSV) and PI3K‐γ (PDB ID: 5G55), obtained from the Protein Data Bank (PDB), were used as the templates for minimization for these respective kinases. The 3D structures of the kinase domain for the other kinases, namely ATR, ATM and DNA‐PK, were prepared by homology modelling using the SWISS‐MODEL server in the similar way as per previously reported parameters, followed by minimization and validation of the same [31] . The template proteins for homology modelling of ATR, ATM and DNA‐PK were selected from the previously reported models, corresponding to the PDB IDs 4JSP, 7NI5, and 7 K0Y, respectively [32–34] …”

“…The 3D structures of the kinase domain for the other kinases, namely ATR, ATM and DNA-PK, were prepared by homology modelling using the SWISS-MODEL server in the similar way as per previously reported parameters, followed by minimization and validation of the same. [31] The template proteins for homology modelling of ATR, ATM and DNA-PK were selected from the previously reported models, corresponding to the PDB IDs 4JSP, 7NI5, and 7 K0Y, respectively. [32][33][34] 2D sketcher tool was used to incorporate all the designed molecules into the software with Epik (Epik, Schrödinger, LLC, New York, NY, 2021) state penalties in the pH range 7.0 � 2.0, followed by their preparation with minimization in OPLS4 force field, using the LigPrep module (LigPrep, Schrödinger, LLC, New York, NY, 2021).…”