Novel deuterated Mnk1/2 protein degrader VNLG-152R analogs: Synthesis, In vitro Anti-TNBC activities and pharmacokinetics in mice


Professor Vincent Njar and his research group at the University of Maryland designed a novel retinamides that can simultaneously inhibit both AR signaling and MNK mediated eIF4E activation in prostate cancer cells. The lead racemic VNLG-152 also demonstrated strong Mnk-eIF4E/m-TORC1 inhibitory and in vitro anticancer activity in a variety of breast cancer subtypes, among other novel retinamides. Experimental studies in rodents in breast and prostate cancer and its pharmacokinetics, including oral bioavailability in mice, have shown promising anticancer and anti-metastatic properties. Isoprene Pharmaceuticals, Inc. is now conducting additional investigational new drug (IND) studies on VNLG-152R in order to prepare for phase I clinical trials in women with triple-negative breast cancer (TNBC). Deuterium incorporation has been demonstrated to drastically affect the pharmacokinetic and metabolic profiles of the parent non-deuterated drugs, leading to an increase in the deuterated compound’s exposure and perhaps a change in the dose and frequency of administration.

In a new study published in the European Journal of Medicinal Chemistry, University of Maryland School of Medicine researchers Dr. Puranik Purushottamachar, Dr. Elizabeth Thomas, Dr. Retheesh Thankan, and led by distinguished professor Vincent Njar  continued the development of VNLG-152R (1) towards human clinical trials and desired to create new analogues of compound 1 with improved pharmacokinetics and as a strategy to create entirely new chemical entities, thereby extending its patent life. The pharmacokinetics of the new deuterated compounds compared to compound 1 were established after discrete and cassette dosing of all compounds in female mice. In vitro testing included the antiproliferative activities against two TNBC cell lines and the influence on the degradation of Mnk1 and the downstream molecular oncogenic targets in TNBC cell lines.

The authors hypothesized that using compound 8 as a starting material would eliminate the low yielding allylic oxidation step based on their prior experience synthesizing compound 1 from ATRA. They focused on replacing of the C4-H, the three hydrogens in C4-imidazole, and the four hydrogens in amide benzyl fluoride. Similar to the novel technique created for the parent molecule 1, the three-step synthetic methods were used to create each of the seven deuterated compounds (11–17). Notably, the yields for the last steps for all the deuterated analogues were low, which they now blame on the deuterated reagents’ poor solubility. Their substances may provide an advantage over taxane-based chemotherapeutics for TNBC because to their equal efficacy to paclitaxel and lack of systemic toxicity. By using Western blotting analysis, the deuterated analogues were also investigated for their effects on the degradation of Mnk1 and the other associated downstream molecular targets in MDA-MB-231 and MDA-MB-468 TNBC cells. Compound 1 and the deuterated analogues dramatically and dose-dependently decreased the expression of Mnk1 and peIF4E in the MDA-MB-231 cells, but had no discernible effects on the expression of total eIF4E or the structural protein β-actin. The substances also significantly reduce the amount of the downstream target, cyclin D1, and induce apoptosis by significantly upregulating proapoptotic Bax and downregulating antiapoptotic Bcl-2. The goal of the deuterated compounds was to create novel, powerful Mnk1/2 degraders with enhanced pharmacokinetics, and they achieved this goal in full. The plasma levels versus time profiles demonstrate that the two deuterated molecules 11 and 15, as well as the non-deuterated compound 1, are swiftly removed from the systemic circulation since they were undetectable 8 hours after delivery. The fact that compounds 11 and 15 had extremely low systemic exposures, compared to 1, which had the best Cmax and AUC, is particularly noteworthy.

In summary, the study by professor Vincent Njar  and his colleagues offers a compelling case for further research and development into the three deuterated chemicals’ potential to test in cancer xenograft models. Furthermore, it is crucial to emphasize that the wholly novel chemical entities created by this deuteration approach will surely support the new patent applications to safeguard the ongoing development of these potential deuterated molecules.


Purushottamachar P, Thomas E, Thankan RS, Njar VC. Novel deuterated Mnk1/2 protein degrader VNLG-152R analogs: Synthesis, In vitro Anti-TNBC activities and pharmacokinetics in mice. A strategy for extending the half-life and patent life of VNLG-152R. European Journal of Medicinal Chemistry. 2022 May 14:114441.

Go To European Journal of Medicinal Chemistry.