Non-NAD-like PARP-1 inhibitors in prostate cancer treatment

Structurally unique PARP‐1 inhibitors for the treatment of prostate cancer

“…The reason for doing so is that our previously identified lead compound, 5F02, is also flagged by a quaternary nitrogen toxicity alert, yet is shown to be safe in vivo 3 . We also needed to adjust the predicted lipophilicity and solubility values to more closely approximate values that we obtained empirically (Figure 2B,C) 4 . These observations underscore that data produced by in silico screening algorithms must be interpreted with caution, and in the context of the specific application.…”

“…With respect to lipophilicity and water solubility, the database provides values using several different algorithms. To determine which algorithm was most appropriate for our use, we queried compounds in which we had previously performed wet physicochemical studies 4 and compared the predicted results to the actual values. Lipophilicity (cLogP) was most closely approximated by averaging the output of two computational algorithms, xLogP3 and wLogP (Figure 2B).…”

“…(A) Chemical diversity of top 66 compounds identified by cellular migration assay, prior to in silico screening by SWISS‐ADME. (B) Comparison of cLogP values obtained empirically for compounds 5F02, FC‐7220, MC270016, MC270017, MC270019, MC270021 ( 4 ), and SWISS‐ADME predicted values using xLogP3, wLogP, or the average of both predicted values. (C) Comparison of solubility values (‐Log(S)) obtained empirically for the compounds described in (B), compared to solubility values predicted by the SWISS‐ADME SILICOS‐IT method, and adjustment of those values (SILICOS‐IT_Adj).…”

“…Using 3D chemical fingerprint clustering of the positive hits, a single compound with the least structural similarity to any known PARP‐1 inhibitor was selected. This compound, 5F02, has been tested in vitro and in vivo, and is currently undergoing further preclinical development 3,4 . Here, we utilize a screening strategy that integrates cellular screening, informatics, computational approaches, and dose‐response testing to reduce the remaining 664 small molecules to the top 9 candidates for further development.…”

α‐Aminophosphonates as Potential PARP1 Inhibitors

“…These interactions with other pathways are often correlated to some of the unwanted side effects and toxicities of PARP1 inhibitors . The concept of a non‐NAD‐like PARP1 inhibitor that targets the activation mechanism which is unique to the PARP1 enzyme only has the potential to alleviate or reduce these unwanted side effects . This paper will report on a novel class of PARP1 inhibitors, the α‐aminophosphonates.…”