QSAR studies of new pyrido[3,4-b]indole derivatives as inhibitors of colon and pancreatic cancer cell proliferation

Abstract

We have discovered a new class of pyrido[b]bindole derivatives that show potent and broad spectrum anticancer activity with IC50 values down to submicromolar levels. Structure-activity relationship data acquired with the compounds as antiproliferative agents against several cancer cell lines, i.e. human HCT116 colon cancer cell line, and HPAC, Mia-PaCa2 and Panc-1 pancreatic cancer cell lines, were subjected to two different QSAR modeling methods. A kernel-based partial least squares (KPLS) regression analysis with chemical 2D fingerprint descriptors, and a PHASE pharmacophore alignment with 3D-QSAR study. The KPLS method afforded successful predictive QSAR models for antiproliferative activity of the HCT116 colon cell line and on two of the pancreatic cancer cell lines HPAC and Mia-PaCa2, with the following statistics: R2s of 0.99, 0.99 and 0.98, for training set coefficients of determination, and external test set predictive r2s of 0.70, 0.58 and 0.70, respectively. The best 2D fingerprint descriptor for both the HCT116 and HPAC data out of the eight finger prints utilized was the atom triplet fingerprint; whereas the one that worked best for the Mia-PaCa2 data was the linear fingerprint descriptor. The PHASE pharmacophore based 3D-QSAR study afforded a four-point pharmacophore model comprising one hydrogen bond donor (D) and three ring (R) elements, which yielded a successful 3D-QSAR model only with the HCT116 cell line data with training set R2 of 0.683, and an external test set predictive r2 of 0.562. With the PHASE 3D-QSAR, the influence of electronic effects and hydrophobicity were visualized, and were in agreement with the observed SAR of substitutions, while the KPLS method the relative extent of contribution of each atom in a compound to the activity. These models will foster the lead optimization process for this potent series of anticancer pyrido [3,4-b]indole compounds.

Targeting MDM2 for novel molecular therapy: Beyond oncology

“…Other types of MDM2 inhibitors, especially those that directly inhibit MDM2 itself, for example, SP141, JapA, and MA242, should be evaluated for their therapeutic efficacy and safety, as they may provide stronger activity by blocking both the p53‐dependent and p53‐independent functions of MDM2. Further evaluation and development of MDM2 inhibitors for cancer therapy are underway . These studies will provide proof‐of‐principle results to support the therapeutic value of this targeting strategy in drug discovery and may greatly contribute to the development of new therapeutics to treat noncancer diseases.…”

Machine Learning on DNA-Encoded Library Count Data Using an Uncertainty-Aware Probabilistic Loss Function

“…The ability to interpret what has been learned by an SAR model can improve the utility of its predictions for medicinal chemists. − In particular, SAR model interpretation allows researchers to understand the rationale behind top predicted compounds and may facilitate the rational design of more potent binders that can be experimentally validated. As fingerprint-based models are especially conducive to substructure-based interpretation, we explored two ways of visualizing the learned SAR of our fingerprint-based feed-forward networks: atom-centered Gaussian visualizations (Figure a) and fingerprint bit and substructure importance (Figure b).…”

Targeting MDM2 for Neuroblastoma Therapy: In Vitro and In Vivo Anticancer Activity and Mechanism of Action

“…Our lab has a long history of developing novel strategies to target MDM2 for cancer therapy and prevention [40][41][42]. In the past, we have identified natural product MDM2 inhibitors such as genistein [43], curcumin [44], and ginsenosides [45][46][47][48][49][50][51][52], and also discovered small-molecule synthetic MDM2 inhibitors such as the SP series [33][34][35][36][53][54][55][56] and synthetic iminoquinones [57][58][59][60][61][62], which have proven effective against several different malignancies. The present study is the first to report the in vitro and in vivo anti-neuroblastoma effects of SP141, a potent and selective MDM2 inhibitor discovered in our lab.…”