Androgen Receptors (AR) constitute an essential nuclear hormone receptor situated within the steroid receptor superfamily.[1] This protein holds immense significance in the modulation of male sexual maturation and functionality, exerting a pivotal influence on the proliferation and sustenance of the prostate gland, alongside the establishment of secondary sexual attributes.[2] The AR is widely expressed in various tissues, including the prostate, testes, skin, and brain, indicating its diverse physiological roles beyond male sexual differentiation. Dysregulation of the AR signaling pathway has been associated with the pathogenesis of various diseases, including prostate cancer, androgenic alopecia, and hirsutism. Consequently, the therapeutic strategy of targeting AR has garnered significant attention in the academic community. Fig. 1 and Table 1.

In recent times, there has been a significant surge in the intensive exploration of small-molecule drugs that specifically target AR.[3], [4], [5] One of the most well-known and widely used small-molecule drugs targeting AR is Bicalutamide.[6] Bicalutamide, an FDA-approved medication for advanced prostate cancer, has demonstrated remarkable clinical efficacy in enhancing patients' overall survival and quality of life. Bicalutamide, exerts its mechanism of action through competitive binding to the AR, thereby impeding the binding of endogenous androgens. Consequently, this impediment of AR activation results in the suppression of androgen-dependent gene transcription, ultimately leading to the inhibition of tumor growth in prostate cancer. Another clinically approved small-molecule drug targeting AR is Enzalutamide.[7] Enzalutamide, as an AR antagonist, exerts its mechanism of action through the inhibition of androgen binding to the receptor and subsequent hindrance of its nuclear translocation. It also prevents the recruitment of coactivators required for AR-mediated gene transcription. Enzalutamide has demonstrated superior efficacy compared to Bicalutamide in preclinical and clinical studies, leading to its approval by the FDA to treat metastatic castration-resistant prostate cancer.[8] In addition to Bicalutamide and Enzalutamide, other small-molecule drugs targeting AR have also been developed and clinically approved. These include Apalutamide and Darolutamide, which have shown similar mechanisms of action and clinical efficacy in the treatment of prostate cancer.[6], [9] These drugs have been shown to delay disease progression, improve survival outcomes, and reduce the risk of metastasis in patients with advanced prostate cancer. Apart from prostate cancer, small-molecule drugs targeting AR have also shown potential in the treatment of other androgen-related disorders. For instance, finasteride and dutasteride are inhibitors of the enzyme 5-alpha-reductase, which impedes the conversion of Testosterone into dihydrotestosterone (DHT), consequently leading to a decrease in the levels of accessible DHT that can bind to and activate the AR.[10], [11], [12], [13].

The rapid development of small-molecule drugs targeting AR has revolutionized the treatment of various androgen-related disorders, particularly prostate cancer. These drugs, such as Bicalutamide, Enzalutamide, Apalutamide, and Darolutamide, have shown significant clinical efficacy in improving overall survival, delaying disease progression, and improving quality of life in patients. Furthermore, they have also demonstrated potential in the treatment of other androgen-related conditions, including androgenic alopecia and benign prostatic hyperplasia. Continued research and development in this field are expected to lead to the discovery of novel and more effective small-molecule drugs targeting AR, further improving patient outcomes, and expanding the therapeutic options available. This review aims to provide an overview of the synthesis and application of clinically approved small-molecule drugs targeting AR. Through integration with prior published reviews, [14], [15], [16] we anticipate that this exhaustive assessment will significantly contribute to advancing the development of small-molecule drugs targeting AR.