百济神州AR靶向PROTAC专利公开《DEGRADATION OF ANDROGEN RECEPTOR (AR) BY CONJUGATION OF AR ANTAGONISTS WITH E3 LIGASE LIGAND AND METHODS OF USE》

 近日，百济神州公开了其双功能AR PROTAC降解剂专利公开，该专利（WO2021058017）最早申请于2019年9月，通过招募E3泛素连接酶来降解AR。

化合物结构通式：

实施例结构摘取部分如下：

根据此前Arvinas报道：

ARV-110 robustly degrades AR in all cell lines tested, with an observed halfmaximal degradation concentration (DC50) of ~1 nM.

“

Proteolysis-targeting chimera (PROTAC) is a novel strategy for selective knockdown of target proteins by small molecules (Sakamoto KM et al., Proc Natl Acad Sci 2001, 98: 8554–9.; Sakamoto K.M. et al., Methods Enzymol. 2005; 399: 833‐847. ) . PROTAC utilizes the Ubiquitin‐protease system to target a specific protein and induce its degradation in the cell (Zhou P. et al., Mol Cell. 2000; 6 (3) : 751‐756; Neklesa T.K. et al., Pharmacol Ther. 2017; 174: 138‐144; Lu M. et al., Eur J Med Chem. 2018; 146: 251‐259; ) . The normal physiological function of the Ubiquitin-protease system is responsible for clearing denatured, mutated, or harmful proteins in cells. The normal physiological function of the Ubiquitin-protease system is responsible for clearing denatured, mutated, or harmful proteins in cells. The Ubiquitin-proteasome system (UPS) , also known as the Ubiquitin-proteasome pathway (UPP) , is a common posttranslational regulation mechanism that is responsible for protein degradation in normal and pathological states (Ardley H. et al., Essays Biochem. 2005, 41, 15-30; Komander D. et al., Biochem. 2012, 81, 203-229; Grice G.L. et al., Cell Rep. 2015, 12, 545-553; Swatek K.N. et al., Cell Res. 2016, 26, 399-422) . Ubiquitin, which is highly conserved in eukaryotic cells, is a modifier molecule, composed of 76 amino acids, that covalently binds to and labels target substrates via a cascade of enzymatic reactions involving E1, E2, and E3 enzymes. Subsequently, the modified substrate is recognized by the 26S proteasome complex for Ubiquitination-mediated degradation. So far, two E1 enzymes have been discovered, which are termed UBA1 and UBA6. On the other hand, there are about 40 E2 enzymes and more than 600 E3 enzymes that offer the functional diversity to govern the activity of many downstream protein substrates. However, only a limited number of E3 Ubiquitin ligases have been successfully hijacked for use by small molecule PROTAC technology: the Von Hippel-Lindau disease tumor suppressor protein (VHL) , the Mouse Double Minute 2 homologue (MDM2) , the Cellular Inhibitor of Apoptosis (cIAP) , and cereblon (Philipp O. et al., Chem. Biol. 2017, 12, 2570-2578) .

Bifunctional compounds composed of a target protein-binding moiety and an E3 Ubiquitin ligase-binding moiety have been shown to induce proteasome-mediated degradation of selected proteins. These drug-like molecules offer the possibility of temporal control over protein expression, and could be useful as biochemical reagents for the treatment of diseases. In recent years, this newly developed method has been widely used in antitumor studies (Lu J. et al., Chem Biol. 2015; 22 (6) : 755‐763; Ottis P. et al., Chem Biol. 2017; 12 (4) : 892‐898.; Crews C.M. et al., J Med Chem. 2018; 61 (2) : 403‐404; Neklesa T.K. et al., Pharmacol Ther. 2017, 174: 138‐144.; Cermakova K. et al., Molecules, 2018.23 (8) .; An S. et al., EBioMedicine, 2018.; Lebraud H. et al., Essays Biochem. 2017; 61 (5) : 517‐527.; Sun Y.H. et al., Cell Res. 2018; 28: 779–81; Toure M. et al., Angew Chem Int Ed Engl. 2016; 55 (6) : 1966‐1973; ) ; and has been disclosed or discussed in patent publications, e.g., US20160045607, US20170008904, US20180050021, US20180072711, WO2002020740, WO2014108452, WO2016146985, WO2016149668, WO2016149989, WO2016197032, WO2016197114, WO2017011590, WO2017030814, WO2017079267, WO2017182418, WO2017197036, WO2017197046, WO2017197051, WO2017197056, WO2017201449, WO2017211924, WO2018033556, and WO2018071606.

Prostate cancer (PCa) continues to be a leading cause of cancer-related male death in North America (S.M. Green, Mol. Cell. Endocrinol. 360 (2012) 3-13) . The main driver of this disease is the androgen receptor (AR) –a transcription factor that is induced by steroids to regulate many of the genes that promote tumor growth (N. Lallous, Int. J. Mol. Sci. 14 (2013) , 12496-12519) . The AR, part of the nuclear receptor family, consists of an N-terminal domain (NTD) , followed by a DNA-binding domain (DBD) and C-terminal ligand-binding domain (LBD) (G. Jenster, Mol. Endocrinol. 5 (1991) 1396-1404) . Steroid binding to the LBD signals nuclear localization followed by DBD-mediated AR dimerization and engagement of the activated receptor dimer at androgen response elements (ARE) on target genes. Currently used AR antagonists, such as enzalutamide, block AR activation by interfering with steroid binding to the androgen-binding pocket on the LBD (C.E. Bohl, J. Biol. Chem. 280 (2005) 37747-37754) . Resistance occurs when mutations in the binding pocket render these drugs ineffective, or by expression of constitutively active splice variants entirely lacking the LBD (e.g. AR-V7, 6-9) . Despite improvements in medical treatments over the past three decades, prostate cancer (PCa) remains a significant cause of cancer-related death, and is second only to lung cancer among men in developed countries. (Hamdy, F.C.; N. Engl. J. Med. 2016, 375, 1415-1424; Litwin, M.S.; J. Am. Med. Assoc. 2017, 317, 2532-2542) . In addition to surgery and radiotherapy, androgen deprivation therapies (ADTs) are frontline treatments for prostate cancer patients with high-risk localized disease, and second-generation antiandrogens, such as abiraterone and enzalutamide, have been shown to benefit patients with advanced prostate cancer (Karantanos, T.; Oncogene 2013, 32, 5501-5511; Harris, W.P., Nat. Clin. Pract. Neurol. 2009, 6, 76-85. ) . Nevertheless, patients who progress to metastatic castration-resistant prostate cancer (mCRPC) , a hormone-refractory form of the disease, face a high mortality rate and no cure is currently available (Narayanan, R.; Oncoscience 2017, 4, 175-177; Crowder, C.M.; Endocrinology 2018, 159, 980-993) . The androgen receptor (AR) and its downstream signaling play a critical role in the development and progression of both localized and metastatic prostate cancer. (Sundén, H.; J. Med. Chem. 2015, 58, 1569-1574) Previous strategies that successfully target AR signaling have focused on blocking androgen synthesis by drugs such as abiraterone and inhibition of AR function by AR antagonists such as enzalutamide and apalutamide (ARN-509) . (Oksala, R.; J. Steroid Biochem. Mol. Biol. 2018; Watson, P.A.; Nat. Rev. Cancer 2015, 15, 701-711; Guo, C.; J. Med. Chem. 2011, 54, 7693-7704.; Guerrini, A.; J. Med. Chem. 2014, 57, 7263-7279. Jung, M. E, J. Med. Chem. 2010, 53, 2779-2796, Yamamoto, S.; Bioorg. Med. Chem. 2012, 20, 2338-2352) . However, such agents become ineffective in advanced prostate cancer with AR gene amplification, mutation, and alternate splicing (Lottrup, G.; J. Clin. Endocrinol. Metab. 2013, 98, 2223-2229) . It is very clear, however, that in most patients with CRPC, the AR protein continues to be expressed and tumors are still dependent on AR signaling. Consequently, AR is an attractive therapeutic target for mCRPC (Munuganti, R.S.; Chem. Biol. 2014, 21, 1476-485) .

There is a need of new AR antagonists which are more potent than known antagonists of AR and antagonize AR via alternative strategies, such as through degradation of AR. The present application addresses the need.

”