Figure
1 | Restoration of androgen receptor signaling. A
| Androgen receptor reactivation. The mechanism of Enz in CRPC
is shown in the left part of the cell. Various signalling pathways
contribute to the activation of AR transcription and expression,
involving FOXA1/CREB5/AR, IKBKE/Hippo/c-Myc/AR, and EphB4/c-Myc/AR
pathways. Several inhibitors, which are associated with AR expression or
targets of relevant pathways, are shown in red arrows. Especially,
ARCC-4, UT-34, and IRF8 are AR degraders that directly act on AR.B | Androgen receptor splice variants and mutations.
The truncated AR with a deleted LBD fails to bind with Enz. AR-V7 is the
most common variant participating multiple signalling pathways, which
are shown in black arrows. AR mutations contain F876L, F877L, H875Y,
T878A/D891H, and T878A/S889G. Some of them can result in the alteration
of Enz function that covert Enz into an agonist. Enz, enzalutamide; AR,
androgen receptor; N, N-terminal domain; D, DNA-binding domain; L,
carboxy-terminal ligand-binding domain; KLK3, kallikrein-related
peptidase 3; TMPRSS2, transmembrane protease serine 2; BMI1, a polycomb
group protein; PTC209, a BMI1 inhibitor; CREB5, cAMP-response
element-binding protein 5; FOXA1, forkhead box protein A1; IKBKE,
I-kappa-B kinase; Eph, erythropoietin-producing human hepatocellular;
4EBP1, eukaryotic initiation factor 4E-binding protein 1; eIF4F,
eukaryotic translation initiation factor 4F, including eIF4A, eIF4E, and
eIF4G; STAT3, signal transducer and activator of transcription 3; JAK,
Janus kinase; GPA500, STAT3 inhibitor; Triptolide, AR/AR-Vs
transactivation activity inhibitor; ARCC-4, proteolysis-targeting
chimaeras (PROTACs) derivative; UT-34, the orally bioavailable AR
degrader; IRF8-induced drugs,
interferon regulatory factor 8;
AR-V7, androgen receptor variant 7; AR-FL, full-length androgen
receptor; hnRNPA1, splicing factor; ACK1, non-receptor tyrosine kinases;
pY88-H4, Tyr88-phosphorylated histone H4; MLL2, a H3K4methyltransferase;
WDR5, MLL2-interacting protein; AVPR1A, arginine vasopressin receptor
1a; VAV3, a Rho family guanosine triphosphatase guanine nucleotide
exchange factor; SPT, supraphysiological testosterone; E2F, the
transcription factor; DDR, DNA damage response; EZH2, zeste homologue 2;
HSP, heat shock protein; STUB1, E3 ubiquitin ligase; AKR1C3, aldo-keto
reductase family 1 member C3; BCL2, B cell lymphoma-2; ABT263, BCL2
protein inhibitor; USP26, ubiquitin specific protease 26; IPI-9119,
fatty acid synthase inhibitor; Luteolin, AR-V7 inhibitor; GATA2, GATA
binding protein 2; BET, bromodomain and extra-terminal; JQI/I-BET762,
small-molecule BET inhibitor; BRD4, amino-terminal bromodomains of
bromodomain-containing protein 4; ZFX, zinc-finger transcription factor;
PARP, poly ADP-ribose polymerase; H12, helix 12; ASC-J9®, AR degradation
enhancer; JJ-450, a AR antagonist.