Targeting the RT loop of Src SH3 in Platelets Prevents Thrombosis without Compromising Hemostasis. Issue 7 (12th January 2022) - Mao, Jianhua
Abstract: Conventional antiplatelet agents indiscriminately inhibit both thrombosis and hemostasis, and the increased bleeding risk thus hampers their use at more aggressive dosages to achieve adequate effect. Blocking integrin α IIb β 3 outside‐in signaling by separating the β 3/Src interaction, yet to be proven in vivo, may nonetheless resolve this dilemma. Identification of a specific druggable target for this strategy remains a fundamental challenge as Src SH3 is known to be responsible for binding to not only integrin β 3 but also the proteins containing the PXXP motif. In vitro and in vivo mutational analyses show that the residues, especially E97, in the RT loop of Src SH3 are critical for interacting with β 3. DCDBS84, a small molecule resulting from structure‐based virtual screening, is structurally validated to be directed toward the projected target. It specifically disrupts β 3/Src interaction without affecting canonical PXXP binding and thus inhibits the outside‐in signaling‐regulated platelet functions. Treatment of mice with DCDBS84 causes a profound inhibition of thrombosis, equivalent to that induced by extremely high doses of α IIb β 3 antagonist, but does not compromise primary hemostasis. Specific targets are revealed for a preferential inhibition of thrombosis that may lead to new classes of potent antithrombotics without hemorrhagic side effects. Abstract : Patients receiving aggressive treatment with conventional antiplatelet agents are subject to the risk of bleeding. DCDBS84, a small molecule specifically targeting c‐Src SH3 RT‐loop around E97, achieves a potent antithrombotic effect without compromising primary hemostasis by selectively blocking outside‐in signaling through integrin α IIb β 3. A new strategy for the development of antithrombotic therapies is provided here.