Design, Synthesis, and Biological Evaluation of Icaritin Derivatives as Novel Putative DEPTOR Inhibitors for Multiple Myeloma Treatment

Abstract

Icaritin is an active ingredient in Epimedium, which has a variety of pharmacological activities. However, the low activity of Icaritin and the unclear target greatly limit its application. Therefore, based on the structure of Icaritin, we adopted the strategy of replacing toxic groups and introducing active groups to design and synthesize a series of new analogues. The top compound C3 exhibited better antimultiple myeloma activity with an IC50 of 1.09 μM for RPMI 8226 cells, induced RPMI 8226 apoptosis, and blocked the cell cycle in the S phase. Importantly, transcriptome analysis, cellular thermal shift assay, and microscale thermophoresis assay confirmed that DEPTOR was the target of C3. Moreover, we explored its binding mode with C3. Especially, C3 displayed satisfactory inhibition of tumor growth in RPMI 8226 xenografts without obvious side effects. In summary, C3 was discovered as a novel putative inhibitor of DEPTOR for the treatment of multiple myeloma.

Is It Still Possible to Think about HSP70 as a Therapeutic Target in Onco-Hematological Diseases?

“…In addition, small molecules were designed to target protein abundance using small mRNA splice modulation and protein degradation rather than using the inhibitory mechanism against a specific protein [ 7 ]. Other small molecules interacting with the mTOR pathway, such as icaritine analogues, bypassed the low activity and off-target limits, providing a new tool in anti-multiple myeloma (MM) therapy [ 8 ]. Chronic lymphocytic leukemia, lastly, is a good example of how translational research has brought targeted drugs to the clinic such as ibrutinib, acalabrutinib and zanubrutinib (Btk inhibitor), and venetoclax (Bcl-2 inhibitor).…”

Discovery of Novel Phosphoinositide-3-Kinase α Inhibitors with High Selectivity, Excellent Bioavailability, and Long-Acting Efficacy for Gastric Cancer

“…After the cells in a 96-well plate were treated with the compound for 72 h, the antiproliferative activity of the compound was detected by CCK8 kit. A synergy H1 (BioTek) microplate reader was used to detect the absorbance value, and GraphPad Prism 8.0 was used to fit the IC 50 curve according to the absorbance value …”

“…1 H NMR (400 MHz, DMSO-d 6 ) δ 11.75 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.33 (dd, J = 8.5, 1.7 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 3.90−3.65 (m, 16H), 2.24 (s, 3H). 13 (23). 27 (383 mg, 1 mmol) and methyl isobutyryl chloride (125 μL, 1.2 mmol) were converted to the target compound following the general procedure.…”

“…A synergy H1 (BioTek) microplate reader was used to detect the absorbance value, and GraphPad Prism 8.0 was used to fit the IC 50 curve according to the absorbance value. 23 Cell Apoptosis Analysis. After the cells in the six-well plate were treated with compounds for 36 h, the samples were detected and analyzed by annexin V-FITC kit and flow cytometry (Becton Dickinson FACS Calibur), and the offline data were analyzed by FlowJo.…”

“…These results indicated that compounds bearing hydrogen-bond acceptors and hydrogen-bond donors have better kinase activity. Moreover, we also obtained a number of amide products 22−25 and found that the activities were significantly increased (22 compared to lead compound), but when the amide substituent becomes bulky (23,24) and rigid (25), the activities were significantly decreased, especially the benzoamide substituent, and the activity of compound 25 was completely lost. Furthermore, the activities were also significantly decreased when the hydrogen of amino groups on the benzoxazole were replaced with two methyl groups (26).…”