HST-1021

HST-1021 is a novel, oral, small molecule allosteric inhibitor targeting the scaffolding function of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1). Developed by HotSpot Therapeutics using their proprietary Smart Allostery platform, HST-1021 is designed to selectively inhibit MALT1’s scaffolding activity within the CARD11-BCL10-MALT1 (CBM) complex—a key regulator of NF-kB signaling in B and T cells—while sparing its protease function. This selective inhibition results in potent suppression of NF-kB and AP-1 activity without depleting regulatory T cells or impairing T-cell function. The drug has demonstrated robust preclinical anti-tumor activity in models of hematological malignancies such as Non-Hodgkin’s lymphoma and selected solid tumors driven by aberrant NF-kB signaling. As a first-in-class agent with a differentiated safety profile compared to traditional MALT1 protease inhibitors, HST-1021 represents a precision oncology approach for cancers mediated by CBM signalosome activation[1][3][5][7][9][10].