Arginase 1/2 inhibitor OATD-02: from discovery to first-in-man setup in cancer immunotherapy.
Bartlomiej BorekJulita NowickaAnna GzikMarek DziegielewskiKarol JedrzejczakJoanna BrzezinskaMarcin Mikołaj GrzybowskiPaulina StanczakPaulina PomperAgnieszka ZagozdzonTomasz Piotr RejczakKrzysztof MatyszewskiAdam GolebiowskiJacek OlczakKamil LisieckiMagdalena TyszkiewiczMagdalena KaniaSylwia PiaseckaAnna CabajPaulina DeraKrzysztof MulewskiJacek ChrzanowskiDamian KusmirekElzbieta SobolewskaMarta MagdyczLukasz MuchaMarek MasnykJakub GolabMarcin NowotnyElzbieta NowakAgnieszka Napiorkowska-GromadzkaStanislaw PikulRadosław JaźwiecKarolina DzwonekPawel DobrzanskiMichael MeyringKrzysztof SkowronekPiotr IwanowskiZbigniew ZaslonaRoman BłaszczykPublished in: Molecular cancer therapeutics (2023)
Pharmacological inhibition of the controlling immunity pathway enzymes arginases 1 and 2 (ARG1 and ARG2) is a promising strategy for cancer immunotherapy. Here, we report the discovery and development of OATD-02, an orally bioavailable, potent arginases inhibitor. The unique pharmacological properties of OATD-02 are evidenced by targeting intracellular ARG1 and ARG2, as well as long drug-target residence time, moderate to high volume of distribution, and low clearance which may jointly provide a weapon against arginase-related tumor immunosuppression and ARG2-dependent tumor cell growth. OATD-02 monotherapy had an antitumor effect in multiple tumor models and enhanced an efficacy of the other immunomodulators. Completed non-clinical studies and human pharmacokinetic predictions indicate a feasible therapeutic window and allow for proposing a dose range for the first-in-human clinical study in cancer patients.