Protecting Bone Marrow with G1T28-1: A Novel CDK 4/6 Inhibitor for Chemotherapy

G1T28-1 is a small molecule inhibitor of cyclin-dependent kinases 4/6 (CDK4/6) that has reached the clinical stage. It is designed to be highly potent and selective, with favorable pharmacological properties to cause a predictable and transient halt in the proliferation of hematopoietic stem and progenitor cells (HSPC). This halt aims to shield HSPC from the DNA damage induced by chemotherapies, thereby preserving these cells and mitigating chemotherapy-induced myelosuppression (CIM), a significant toxicity limiting the dosage of many anticancer drugs.

Biochemical profiling indicates that G1T28-1 competitively inhibits CDK4/6 at low nanomolar concentrations and is particularly selective for CDK4/cyclin D1 and CDK6/cyclin D3 complexes. The compound induces a clear G0/G1 phase arrest in CDK4/6-dependent cell lines in vitro. G1T28-1 was found to completely prevent the phosphorylation of the retinoblastoma protein (Rb) in these cell lines within 16 hours, an effect not observed in CDK4/6-independent cells.

The compound's impact on cells is temporary and reversible; after a 24-hour treatment with G1T28-1, cells arrested in the cell cycle re-enter it within 16 hours post-washout, maintaining normal cell cycle progression. G1T28-1's ability to lessen DNA damage and apoptosis following chemotherapy was demonstrated by reduced γ-H2AX formation and caspase 3/7 activation in a dose-dependent manner.

In the context of Rb null cancers, such as small cell lung cancer (SCLC), G1T28-1 may protect HSPC without compromising the effectiveness of chemotherapy. In vitro tests with SCLC cell lines confirmed that the addition of G1T28-1 did not affect the efficacy of chemotherapy.

In summary, G1T28-1 is a novel CDK4/6 inhibitor capable of inducing a transient and reversible G0/G1 cell cycle arrest in CDK4/6-sensitive cells, potentially reducing CIM without affecting the anti-tumor activity of chemotherapy in CDK4/6-resistant cells.