1. Design and characterization of cereblon-mediated androgen receptor proteolysis-targeting chimeras
Akshay D Takwale, Seung-Hyun Jo, Yeong Uk Jeon, Hyung Soo Kim, Choong Hoon Shin, Heung Kyoung Lee, Sunjoo Ahn, Chong Ock Lee, Jae Du Ha, Jeong-Hoon Kim, Jong Yeon Hwang Eur J Med Chem. 2020 Dec 15;208:112769.doi: 10.1016/j.ejmech.2020.112769.Epub 2020 Aug 26.
Proteolysis-targeting chimera (PROTAC)-mediated protein degradation is a rapidly emerging therapeutic intervention that induces the degradation of targeted proteins. Herein, we report the design and biological evaluation of a series of androgen receptor (AR) PROTAC degraders for the treatment of metastatic castration-resistant prostate cancer. Predominantly, instead of thalidomide, we utilized the TD-106 scaffold, a novel cereblon (CRBN) binder that was identified in our previous study. Our results suggest that the linker position in the TD-106 CRBN binder is critical for the efficiency of AR degradation. The compounds attached to the 6-position of TD-106 promoted better degradation of AR than those at the 5- and 7-positions. Among the synthesized AR PROTACs, the representative degrader 33c (TD-802) effectively induced AR protein degradation, with a degradation concentration 50% of 12.5 nM and a maximum degradation of 93% in LNCaP prostate cancer cells. Additionally, most AR PROTAC degraders, including TD-802, displayed good liver microsomal stability and in vivo pharmacokinetic properties. Finally, we showed that TD-802 effectively inhibited tumor growth in an in vivo xenograft study.
2. Structure-activity relationship analysis of novel GSPT1 degraders based on benzotriazinone scaffold and its antitumor effect on xenograft mouse model
Akshay D Takwale, Eun Yeong Kim, Yerin Jang, Dong Ho Lee, Seulgi Kim, Yuri Choi, Jin Hwan Kim, Da Yeon Lee, Yeongrin Kim, So Myoung Lee, Heung Kyoung Lee, Hye Jin Nam, Joo-Youn Lee, Jin Hwa Cho, Jeong Hee Moon, Ga Seul Lee, Jeong-Hoon Kim, Pilho Kim, Chi Hoon Park, Jong Yeon Hwang Bioorg Chem. 2022 Oct;127:105923.doi: 10.1016/j.bioorg.2022.105923.Epub 2022 Jun 13.
Molecular glue degraders, such as lenalidomide and pomalidomide, bind to cereblon (CRBN) E3 ligase and subsequently recruit neosubstrate proteins, Ikaros (IKZF1) and Aiolos (IKZF3), for the ubiquitination-proteasomal degradation process. In this study, we explored structure-activity relationship analysis for novel GSPT1 degraders utilizing a benzotriazinone scaffold previously discovered as a novel CRBN binder. In particular, we focused on the position of the ureido group on the benzotriazinone scaffold, substituent effect on the phenylureido group, and methyl substitution on the benzylic position of benzotriazinone. As a result, we identified 34f (TD-522), which exhibits strong anti-proliferative effects in both KG-1 (EC50 = 0.5 nM) and TMD-8 (EC50 = 5.2 nM) cell lines. Compound 34f effectively induced GSPT1 degradation with a DC50 of 0.269 nM and Dmax of >95 % at 10 nM concentration in KG-1 cells. An in vivo xenograft study showed that compound 34f effectively suppressed TMD8-driven tumor growth, suggesting a potential role in the development of novel GSPT1 degraders.
3. A novel cereblon modulator for targeted protein degradation
Sung Ah Kim, Ara Go, Seung-Hyun Jo, Sun Jun Park, Young Uk Jeon, Ji Eun Kim, Heung Kyoung Lee, Chi Hoon Park, Chong-Ock Lee, Sung Goo Park, Pilho Kim, Byoung Chul Park, Sung Yun Cho, Sunhong Kim, Jae Du Ha, Jeong-Hoon Kim, Jong Yeon Hwang Eur J Med Chem. 2019 Mar 15;166:65-74.doi: 10.1016/j.ejmech.2019.01.023.Epub 2019 Jan 17.
Immunomodulatory drugs (IMiDs) exert anti-myeloma activity by binding to the protein cereblon (CRBN) and subsequently degrading IKZF1/3. Recently, their ability to recruit E3 ubiquitin ligase has been used in the proteolysis targeting chimera (PROTAC) technology. Herein, we design and synthesize a novel IMiD analog TD-106 that induces the degradation of IKZF1/3 and inhibits the proliferation of multiple myeloma cells in vitro as well as in vivo. Moreover, we demonstrate that TD-428, which comprises TD-106 linked to a BET inhibitor, JQ1 efficiently induce BET protein degradation in the prostate cancer cell line 22Rv1. Consequently, cell proliferation is inhibited due to suppressed C-MYC transcription. These results, therefore, firmly suggest that the newly synthesized IMiD analog, TD-106, is a novel CRBN modulator that can be used for targeted protein degradation.
CAS No.: 2250288-69-6
