Boston – November 10, 2026 -- HotSpot Therapeutics reported preclinical data showing that its oral IRF5 inhibitor HST-2011 suppressed three disease-driving pathways in systemic lupus erythematosus (SLE) across human cell systems, human whole blood and cynomolgus monkeys. The data were presented in a poster at ACR Convergence 2026.
HST-2011 reduces B cell, interferon and cytokine readouts in three models
In human cellular systems, HST-2011 inhibited plasmablast formation and IgG production. It also potently inhibited type I interferon and proinflammatory cytokine production, including TNF and IL-1β.
In human whole blood stimulated with a TLR agonist, the compound reduced plasmablast, B-cell activation and interferon gene signature scores. mRNA sequencing showed reduced expression of IFNB1, TNF and IL1B.
After oral dosing in cynomolgus monkeys, ex vivo whole-blood studies showed reductions in plasmablast and interferon gene signature scores, as well as in IFNB1, TNF and IL1B mRNA expression. HotSpot said these results were consistent with the human whole blood findings.
Allosteric design targets a protein that lacks a traditional active site
HST-2011 is an investigational, non-covalent, non-degrading allosteric small molecule inhibitor of interferon regulatory factor 5 (IRF5). Historical efforts to modulate IRF5 with traditional small molecule approaches failed because the protein has no traditional active site.
HotSpot discovered the compound with its proprietary Smart Allostery platform, which combines computational approaches and AI-driven data mining of large data sets to identify natural regulatory pockets.
Genome-wide association studies link IRF5 to SLE, cutaneous lupus erythematosus, Sjögren's disease, rheumatoid arthritis, systemic sclerosis and myositis.
HotSpot plans to advance HST-2011 toward clinical development
Co-Founder and Chief Scientific Officer Geraldine Harriman called IRF5 a "master regulator of innate and adaptive immunity" and said the data support the compound's therapeutic potential. HotSpot intends to advance HST-2011 toward clinical development as a potential oral treatment for autoimmune diseases.