Novel Protein Kinase D inhibitors

As we are going to talk about the Protein Kinase D inhibitors, let’s understand the basic about the protein kinases. Actually they are the enzymes which catalyze protein phosphorylation, i.e., the transfer of the gamma-phosphoryl group of ATP to tyrosine, serine and threonine residues in protein substrates. Phosphorylation can result in activation / inhibition of an enzyme, conformational changes or creation of surface with distinct binding properties. Thus, protein phosphorylation has great role in various cellular processes and defect in this process can result in many diseases including cancer and inflammation.


Recently, researchers from University of Pittsburgh has reported the Novel protein kinase D inhibitors that cause arrest in prostate cancer cell growth and motility.

Protein kinase D is a novel family of serine/threonine kinases and Diacylglycerol (DAG) receptors. Three isoforms has been idenfied as PKD1, 2 and 3. Since its discovery, PKD has been implicated in various cellular functions significant to tumor development including proliferation, survival, apoptosis, angiogenesis, and motility.

In this study, they have synthesized the analogues of CID755673 (previously reported PKD inhibitor) by modifying their core structures and side chains.

SAR study

Design of CID755673 analouges was based on the modification of 4 major structural zones (I, II, III and IV) as shown in figure (right side).

In zone I, phenolic substituent was modified as well as the alpha position on the aromatic ring.

Most of the derivatives were considerably less active than parent compound in the PKD screening.

In zone II, oxygen was changed with sulfur and nitrogen

Nitrogen replacement results in loss of activity, whereas sulfur substitution increases the activity.

In zone III, ring size was modified by adding or removing methylene groups, as well as substituting the benzylic positions.

Thioether insertion exo to the five-membered heterocycle and an additional methylene group were well tolerated.

In zone IV, functional group interconversions as well as replacement of the amide with heterocyclic groups.

Showed unsatisfactory activity thus amide function of parent compound was retained.

After initial screening and the SAR analysis on ca 50 analogues, five novel compounds with equal or greater potency for PKD compared to parent compound were selected for further testing.

Among the analogues, kb-NB142-70 was the most potent compound which inhibited PKD1 with nearly 7-fold greater potency compared to parent compound (CID755673). It also, inhibited PKD2 and PKD3 about 4-fold stronger than parent compound

It has been found that these analogs showed increased cytotoxicity and dramatic arrest in cell proliferation (prostate cancer cells) compared to parent compound. In addition, authors reported that the analogues, Kb-NB142-70 and Kb-NB165-09, in particular, are potent inhibitors of prostate cancer cell migration and invasion.

From their experimental data, researchers concluded that Kb-NB142-70 and Kb-NB165-09 are the most potent and specific analogues in vitro and in cells. They are doing further testing for these compounds in order to find potential anti-cancer agents in the treatment of prostate cancer.