Conventional cytotoxic chemotherapy is highly effective in certain cancers but 
causes dose-limiting damage to normal proliferating cells, especially 
hematopoietic stem and progenitor cells (HSPCs). Serial exposure to cytotoxics 
causes a long-term hematopoietic compromise ("exhaustion"), which limits the use 
of chemotherapy and success of cancer therapy. We show that the coadministration 
of G1T28 (trilaciclib), which is a small-molecule inhibitor of cyclin-dependent 
kinases 4 and 6 (CDK4/6), contemporaneously with cytotoxic chemotherapy protects 
murine hematopoietic stem cells (HSCs) from chemotherapy-induced exhaustion in a 
serial 5-fluorouracil treatment model. Consistent with a cell-intrinsic effect, 
we show directly preserved HSC function resulting in a more rapid recovery of 
peripheral blood counts, enhanced serial transplantation capacity, and reduced 
myeloid skewing. When administered to healthy human volunteers, G1T28 
demonstrated excellent in vivo pharmacology and transiently inhibited bone 
marrow (BM) HSPC proliferation. These findings suggest that the combination of 
CDK4/6 inhibitors with cytotoxic chemotherapy should provide a means to 
attenuate therapy-induced BM exhaustion in patients with cancer.