Protein Degradation Inducers of Androgen Receptor by Conjugation of Antagonists Androgen Receptor and E3 Ligase Ligand

Important Compound Classes

Title

Degradation of Androgen Receptor (AR) by Conjugation of AR Antagonists with E3 Ligase Ligand and Methods of Use.

Patent Publication Number

WO 2021/058017 A1

Publication Date

April 1, 2021

Priority Application

PCT/CN2019/109009 CN

Priority Date

September 29, 2019

Inventors

Huo, C.; Qiu, M.; Wang, Z.

Assignee Company

Beigene, Ltd.; c/o Mourant Governance Services (Cayman) Limited, 94 Solaris Avenue, Camana Bay, Grand Cayman KY1-1108 (KY).

Disease Area

Cancer

Biological Target

Androgen Receptor (AR)

Summary

Prostate cancer (PCa) is one of the deadliest forms of cancer-related death in men in the United States and worldwide. The occurrence and progression of PCa are mainly attributed to the dysregulation of the androgen receptor (AR) signaling. The AR and its downstream signaling play a critical role in the development and progression of both localized and metastatic prostate cancer. Consequently, AR represents the primary therapeutic target and blockage of the androgen signaling has proven to be effective for PCa treatment. AR is part of the nuclear receptor family that consists of an N-terminal domain (NTD), which is followed by a DNA-binding domain (DBD) and a C-terminal ligand-binding domain (LBD).

AR-directed therapeutics such as enzalutamide, darolutamide, and apalutamide can efficiently block the endogenous androgen binding at the androgen binding site of an AR. However, a large proportion of PCa patients respond to this treatment initially but acquire resistance in long-term therapy. This eventually enters a more severe malignancy castration-resistant prostate cancer (CRPC) state. Furthermore, androgen binding site mutations weaken the AR–drug interactions and signaling through diverse mechanisms, which can turn an antagonist into an agonist to promote cancer progression. In addition to surgical or chemical castration by gonadotropin-releasing hormone (GnRH) analogues, AR antagonists in combination with castration demonstrate significant effects toward their use earlier in the disease to more delayed disease progression. Furthermore, androgen deprivation therapies (ADTs) are frontline treatments for prostate cancer patients with high-risk localized disease, and second-generation antiandrogens therapy. Limited biomarkers exist to identify meaningful diagnostics for PCa, resulting in the lack of effective treatment for patients with disease progression with aggressive PCa, which ultimately remains uncured. Also, 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. However, catching and treating the disease early potentially saves lives. The exact mechanisms of progression to CRPC are not always known; however, numerous contributing factors to the emergence of CRPC are proposed, including (1) AR gene amplifications and overexpression; (2) compensatory production of intratumoral androgens; (3) AR ligand binding domain (LBD) point mutations; (4) ligand-independent activation of AR; (5) alterations in the expression of coregulatory proteins; (6) induction of intracrine androgen synthesis; and (7) constitutively active truncated AR splice variants (AR SVs).

In spite of strategies that successfully target AR signaling, such as blocking of androgen synthesis using drugs such as abiraterone, and the inhibition of AR function by AR antagonists such as apalutamide (ARN-509) and enzalutamide, they become ineffective in advanced prostate cancer with AR gene amplification, mutation, and alternate splicing. Nonetheless, in most patients with CRPC, the AR protein continues to be expressed and tumors are still dependent on AR signaling, which still makes AR an attractive therapeutic target for mCRPC. As a result, there is a need for new AR antagonists which are more potent than known antagonists of AR that would antagonize the AR via alternative strategies such as protein degradation.

Proteolysis-targeting chimera (PROTAC) is a novel strategy for the selective knockdown of target proteins by small molecules and utilizes the ubiquitin-protease system to target a specific protein and induce its degradation. The ubiquitin-protease system (UPS) normal physiological function is clearing denatured, mutated, or harmful protein in cells. In addition, the UPS, also known as the ubiquitin-proteasome pathway (UPP), is a common post-translational regulation mechanism that not only degrade normal proteins but pathological proteins as well. Ubiquitin is highly conserved in eukaryotic cells and is composed of 76 amino acids, which covalently binds to and labels target substrates via a cascade of enzymatic reactions involving E1, E2, and E3 enzymes. There are more than 600 E3 enzymes that offer the functional diversity that govern the activity of many downstream protein substrates. Rather, only a limited number of E3 ubiquitin ligases have been successfully utilized for use by small molecules via the PROTAC strategy: the mouse double minute 2 homologue (MDM2), the cellular inhibitor of apoptosis (cIAP), the Von Hippel-Lindau disease tumor suppressor protein (VHL), and cereblon (CRBN). PROTAC molecules are composed of a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety which induce proteasome-mediated degradation of selected proteins. These bifunctional compounds have been successfully used for the treatment of diseases and are widely utilized in antitumor studies. This Patent Highlight showcases novel bifunctional compounds that conjugate AR antagonist moieties with the E3 ligase ligand, which recruits targeted proteins to the E3 ubiquitin ligase for degradation.

Definitions

R₁ and R₃ = hydrogen, halogen, −C_1–8alkyl, −C_2–8alkenyl, −C_2–8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and so forth;

R₂ and R₄ = hydrogen, halogen, −CN, −NO₂, −C_1–8alkyl, −C_2–8alkenyl, −C_2–8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and so forth;

p and t are each independently 0, 1, 2, 3, or 4, single or double bond;

X₁, X_2, X_3, X₄, X₅ is independently CR^d or N and so forth.

Key Structures

Biological Assay

PathScan Total Androgen Receptor Sandwich ELISA Kit.

Biological Data

The table below shows degradation DC₅₀ values for exemplary AR antagonists.

Recent Review Articles

• 1.Ehsani M.; David F. O.; Baniahmad A.. Cancers 2021, 13, 1534.
• 2.Kim T. J.; Lee Y. H.; Koo K. C.. Biomolecules 2021, 11, 492.
• 3.Alabi S. B.; Crews C. M.. J. Biol. Chem. 2021, 296, 100647.
• 4.Tomoshige S.; Ishikawa M.. Angew. Chem. Int. Ed. 2021, 60, 3346.
• 5.Martin-Acosta P.; Xiao X.. Eur. J. Med. Chem. 2021, 210, 112993.
• 6.Bricelj A.; Sosic I.; Steinebach C.; Kuchta R.; Gutschow M.. Front. Chem. 2021, 9, 707317.

The author declares no competing financial interest.