TTLL1 Inhibitors

Chemical inhibitors of TTLL1 target the protein's reliance on microtubule dynamics to exert its tubulin-modifying function. Colchicine, a compound known for its ability to inhibit microtubule polymerization, can hamper the function of TTLL1 by disrupting the formation of the microtubule structures that TTLL1 modifies. Similarly, Nocodazole's action as a microtubule-depolymerizing agent directly impacts TTLL1 by altering the normal polymerization and depolymerization cycle of tubulin, the substrate of TTLL1. Vinblastine and Vincristine, both microtubule-targeting agents, bind to tubulin and prevent its polymerization, which in turn can inhibit TTLL1 as it cannot modify what is not properly assembled. Paclitaxel takes an opposite approach by stabilizing microtubules and preventing their disassembly, thereby indirectly inhibiting TTLL1 by locking its substrate into an inaccessible form, precluding modification.

In the same vein, Podophyllotoxin can inhibit TTLL1 by stabilizing tubulin in a non-polymerized state, preventing the formation of microtubule structures essential for TTLL1's activity. Eribulin exerts its inhibitory effect on TTLL1 by selectively inhibiting the growth phase of microtubules without affecting the shortening phase, leading to improperly formed microtubules and, consequently, inhibition of TTLL1 activity. Peloruside A shares a similar mechanism by stabilizing microtubules, which can inhibit TTLL1 by disallowing the dynamic changes required for its activity. Griseofulvin interferes with microtubule assembly, thus can inhibit the function of TTLL1, which depends on the proper assembly of microtubules to carry out its enzymatic duties. Combretastatin A4 binds to the colchicine site on tubulin, inhibiting its polymerization and potentially preventing TTLL1 from modifying the microtubule network. Finally, Mebendazole and Albendazole both disrupt microtubule formation by targeting tubulin polymerization, which can inhibit TTLL1 since it needs polymerized tubulin to functionally modify the microtubule network.