The Novel Mnk1/2 Degrader and Apoptosis Inducer VNLG-152 Potently Inhibits TNBC Tumor Growth and Metastasis

Currently, there are no effective therapies for patients with triple-negative breast cancer (TNBC), an aggressive and highly metastatic disease. Activation of eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) play a critical role in the development, progression and metastasis of TNBC. Herein, we undertook a comprehensive study to evaluate the activity of a first-in-class Mnk1/2 protein degraders, racemic VNLG-152R and its two enantiomers (VNLG-152E1 and VNLG-152E2) in in vitro and in vivo models of TNBC. These studies enabled us to identify racemic VNLG-152R as the most efficacious Mnk1/2 degrader, superior to its pure enantiomers. By targeting Mnk1/2 protein degradation (activity), VNLG-152R potently inhibited both Mnk-eIF4E and mTORC1 signaling pathways and strongly regulated downstream factors involved in cell cycle regulation, apoptosis, pro-inflammatory cytokines/chemokines secretion, epithelial-mesenchymal transition (EMT) and metastasis. Most importantly, orally bioavailable VNLG-152R exhibited remarkable antitumor (91 to 100% growth inhibition) and antimetastatic (~80% inhibition) activities against cell line and patient-derived TNBC xenograft models, with no apparent host toxicity. Collectively, these studies demonstrate that targeting Mnk-eIF4E/mTORC1 signaling with a potent Mnk1/2 degrader, VNLG-152R, is a novel therapeutic strategy that can be developed as monotherapy for the effective treatment of patients with primary/metastatic TNBC

Systematic Structure Modifications of Multitarget Prostate Cancer Drug Candidate Galeterone To Produce Novel Androgen Receptor Down-Regulating Agents as an Approach to Treatment of Advanced Prostate Cancer

As part of our program to explore the influence of small structural modifications of our drug candidate 3β-(hydroxy)-17-(1<i>H</i>-benzimidazol-1-yl)­androsta-5,16-diene (galeterone, <b>5</b>) on the modulation of the androgen receptor (AR), we have prepared and evaluated a series of novel C-3, C-16, and C-17 analogues. Using structure activity analysis, we established that the benzimidazole moiety at C-17 is essential and optimal and also that hydrophilic and heteroaromatic groups at C-3 enhance both antiproliferative (AP) and AR degrading (ARD) activities. The most potent antiproliferative compounds were 3β-(1<i>H</i>-imidazole-1-carboxylate)-17-(1<i>H</i>-benzimidazol-1-yl)­androsta-5,16-diene (<b>47</b>), 3-((<i>EZ</i>)-hydroximino)-17-(1<i>H</i>-benzimidazol-1-yl)­androsta-4,16-diene (<b>36</b>), and 3β-(pyridine-4-carboxylate)-17-(1<i>H</i>-benzimidazol-1-yl)­androsta-5,16-diene (<b>43</b>), with GI₅₀ values of 0.87, 1.91, and 2.57 μM, respectively. Compared to <b>5</b>, compound <b>47</b> was 4- and 8-fold more potent with respect to AP and ARD activities, respectively. Importantly, we also discovered that our compounds, including <b>5</b>, <b>36</b>, <b>43</b>, and <b>47</b>, could degrade both full-length and truncated ARs in CWR22rv1 human prostate cancer cells. With these activities, they have potential for development as new drugs for the treatment of all forms of prostate cancer

Synthesis and biological evaluation of JAHAs: ferrocene-based histone deacetylase inhibitors

N1-Hydroxy-N8-ferrocenyloctanediamide, JAHA (7), an organometallic analogue of SAHA containing a ferrocenyl group as a phenyl bioisostere, displays nanomolar inhibition of class I HDACs, excellent selectivity over class IIa HDACs, and anticancer action in intact cells (IC50 = 2.4 μM, MCF7 cell line). Molecular docking studies of 7 in HDAC8 (a,b) suggested that the ferrocenyl moiety in 7 can overlap with the aryl cap of SAHA and should display similar HDAC inhibition, which was borne out in an in vitro assay (IC50 values against HDAC8 (μM, SD in parentheses): SAHA, 1.41 (0.15); 7, 1.36 (0.16). Thereafter, a small library of related JAHAanalogues has been synthesized, and preliminary SAR studies are presented. IC50 values as low as 90 pM toward HDAC6 (class IIb) have been determined, highlighting the excellent potential of JAHAs as bioinorganic probes