The cation channels of sperm also known as CatSper channels or CatSper, are ion channels that are related to the two-pore channels ^[1]. In mammals, CatSper subunits are structurally most closely related to individual domains of voltage-activated calcium channels (Cav) ^[2]. CatSper1 ^[2], CatSper2 ^[3] and CatSper3 and CatSper4 ^[4], in common with a putative 2TM auxiliary CatSperβ protein ^[5] and two putative 1TM associated CatSperγ and CatSperδ proteins ^[6], are restricted to the testis and localised to the principle piece of sperm tail. CatSper comprises the pore-forming proteins CATSPER1–4 and multiple auxiliary subunits, including CATSPERβ, γ, δ, ε, ζ, and EFCAB9 ^[7].

CATSPER1–4 conform to the conventional domain-swapped voltage-gated ion channel fold10, following a counterclockwise arrangement. The auxiliary subunits CATSPERβ, γ, δ and ε—each of which contains a single transmembrane segment and a large extracellular domain—constitute a pavilion-like structure that stabilizes the entire complex through interactions with CATSPER4, 1, 3 and 2, respectively ^[8].

The bisphenols BPG, BPAF, BPC, BADGE, BPB, and BPBP can affect Ca²⁺ signaling in human sperm cells through activation of CatSper ^[9].

Compounds impacting male fertility have been predominantly identified from anecdotal and off‐target effects of drugs used for other indications. Examples include anticancer agent lonidamine and related analogs adjudin ^[10] and gamendazole, ^[11] triptolide and triptonide^{[12, 13]}, BET bromodomain inhibitor JQ1, ^[14] ALDH1 A2 inhibitor WIN 18,466, ^[15] originally developed as an amebicide, and retinoic acid receptor antagonists originally developed for dermatological and inflammatory diseases ^[16]. To date, little progress has been made in developing CatSper‐specific blockers. HC‐056456, a CatSper blocker identified through screening, slows the rise of intracellular calcium in sperm and prevents HAM in the low micromolar range ^[11] Mibefradil (Ro 40‐5967) ^[17] and its close structural analog NNC 55‐0396 ^[18] are calcium channel blockers that were originally developed to block T‐ and L‐type channels, and later found to also block CatSper ^[19]. Recently, a synthetic steroidal blocker (RU 1968) of CatSper was reported, displaying micromolar potency and providing a new class of CatSper blockers ^[20].