PROTACCDK4/6/9 degrader 1 is a PROTAC degrader targeting CDK4/6/9. It effectively degrades CDK4, CDK6, and CDK9 within triple-negative breast cancer (TNBC) cells, thereby inhibiting their proliferation. Additionally, PROTACCDK4/6/9 degrader 1 induces G1 phase arrest, promotes apoptosis, and suppresses cell migration and invasion in TNBC cells. This compound is useful for researching triple-negative breast cancer (TNBC).

CDK4:0.71 nM (DC50 , MDA-MB-231 cells)

PROTAC CDK4/6/9 degrader 1 (Compound B5) exhibits potent antiproliferative activity at concentrations of 0.1-1 nM over 96 hours against multiple triple-negative breast cancer (TNBC) cell lines, including MDA-MB-231, CAL51, SUM-159, MDA-MB-453, Hs578T, MDA-MB-468, MDA-MB-436, 4T1, and EO771, with IC50 values of 0.26 nM, 0.21 nM, 0.38 nM, 0.13 nM, 0.27 nM, 0.21 nM, 0.45 nM, 0.53 nM, and 0.59 nM, respectively. Additionally, it demonstrates strong CDK degradation activity in MDA-MB-231 and CAL51 cells at 0.1-1 nM over 24 hours, with DC50 values for CDK4, CDK6, and CDK9 of 0.71 nM, 0.44 nM, and 0.52 nM in MDA-MB-231, and 0.79 nM, 0.61 nM, and 0.51 nM in CAL51. At 1 nM, the compound also shows time-dependent degradation of these CDKs over 3-48 hours in the same cell lines. At 100 nM over 8 hours, it selectively inhibits CDK family members in TNBC cells, achieving 98% inhibition for CDK4/CycD3 and CDK6/CycD3, 92% for CDK9/CycT1, and 91% for CDK6/CycD1, with lesser inhibition of CDK13/CycK (51%) and CDK5/p35NCK (47%). Furthermore, at 0.5-1 nM over 48 hours, the compound displays strong pro-apoptotic activity, notably increasing the percentage of apoptotic cells. It also induces significant G1 phase cell cycle arrest in MDA-MB-231 and CAL51 cells at 0.5-1 nM over 24 hours. Lastly, the compound effectively inhibits migration and invasion in these cell lines at 0.5-1 nM.