MDV3100 (Enzalutamide) (Synonyms: Enzalutamide)

MDV3100(enzalutamide) is a second-generation AR antagonist with an IC₅₀ of 36nM in LNCaP prostate cells^[1,2]. MDV3100 could reduce androgen binding to AR, inhibit AR transport to the nucleus and prevent the binding of AR to androgen response elements^[2].

MDV3100 combined with TKIs exerted a synergistic effect on a variety of PCa cells. MDV3100 combined with afatinib could suppress the proliferation and migration of 22RV1 cells, as well as cause their cell cycle arrest and apoptosis^[2]. MDV3100 probed the bone microenvironment that led to stronger cancer cell adaptive responses and osteomimicry than bicalutamide. MDV3100 presented with better treatment response, in line with MDV3100 delaying time to bone-related events and MDV3100 extending survival in mCRPC^[3]. MDV3100 promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion in human (C4-2B/THP1) and mouse (TRAMP-C1/RAW264.7) PCa cells–macrophages co-culture systems^[4]

MDV3100 combination with KIF15 inhibitors significantly suppressed MDV3100-resistant PCa cell growth and xenograft progression. KIF15 inhibitors may enhance the sensitivity of prostate tumors to MDV3100 treatment, and rationalize a combination therapy of KIF15 inhibitors with MDV3100 to treat CRPC patients ^[5]. The antitumor efficacy of MDV3100 can be substantially improved by methylselenol prodrug, which also downregulates AR-FL and AR-Vs in vivo^[6]. MDV3100 prolonged overall survival of metastatic CRPC patients who progressed after chemotherapy in a Phase III trial^[7]

References:
[1]. Tran C, Ouk S, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324(5928):787-790.
[2]. Li J, Wu H, et al. Enhanced antitumor efficacy by combining afatinib with MDV3100 in castration-resistant prostate cancer. Pharmazie. 2022;77(2):59-66.
[3]. Bock N, Kryza T, et al. In vitro engineering of a bone metastases model allows for study of the effects of antiandrogen therapies in advanced prostate cancer. Sci Adv. 2021;7(27):eabg2564.
[4]. Lin TH, Izumi K, et al. Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 (Enzalutamide) or Casodex (Bicalutamide) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling. Cell Death Dis. 2013;4(8):e764.
[5]. Gao L, Zhang W, et al. KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer. Cancer Res. 2021;81(4):1026-1039.
[6]. Zhan Y, Cao B, et al. Methylselenol prodrug enhances MDV3100 efficacy for treatment of castration-resistant prostate cancer. Int J Cancer. 2013;133(9):2225-2233.
[7]. Scher HI, Fizazi K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-1197.