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Hematopoietic stem cells (HSCs) have emerged as promising therapeutic cell sources for high-risk hematological malignancies and immune disorders. However, their clinical use is limited by the inability to expand these cells  ex vivo . Therefore, there is an urgent need to identify specific targets and effective probes that can expand HSCs. Here we report a novel class of INK4C (p18 INK4C  or p18) small molecule inhibitors (p18SMIs), which were initially found by  in silico  3D screening. We identified a lead p18 inhibitor, XIE18-6, confirmed its p18-targeting specificity and bioactivity of promoting HSCs expansion, and then performed structure-activity relationship (SAR) studies by synthesizing a series of analogs of XIE18–6. Among these, compound  40  showed the most potent bioactivity in HSCs expansion (ED 50  = 5.21 nM). We confirmed that compound  40  promoted expansion of both murine and human HSCs, and also confirmed its p18-targeting specificity. Notably, compound  40  did not show significant cytotoxicity toward 32D cells or HSCs, nor did it augment leukemia cell proliferation. Taken together, our newly discovered p18SMIs represent novel chemical agents for murine and human HSCs  ex vivo  expansion and also can be used as valuable chemical probes for further HSC biology research towards promising utility for therapeutic purposes.

Discovery of novel INK4C small-molecule inhibitors to promote human and murine hematopoietic stem cell ex vivo expansion