Background: Colorectal cancer (CRC) is driven by genetic alterations that result in constitutive activation of oncogenic transcription factors (eg β-catenin, MYC) and of mitogenic signaling and cell cycle progression (driven by oncogenic mutations in KRAS and BRAF). CDK7 is a key regulator of transcription, through phosphorylation of the CTD domain of RNA Polymerase II, and of cell cycle progression, through phosphorylation of the cell cycle kinases CDK1, 2, 4, and 6. This dual role of CDK7 suggests inhibitors of CDK7 may be effective in the treatment of CRC. SY-5609 is an oral, noncovalent, potent and highly selective CDK7 inhibitor in phase 1 clinical development for patients with advanced solid tumors including CRC (NCT04247126). Here we report on the activity of SY-5609 in patient-derived xenograft (PDX) models of CRC. Methods: SY-5609 was administered once daily (QD) by oral gavage for 21 days (end of treatment, EOT) to mice bearing PDX models of CRC. The relationship between SY-5609 dose, pharmacodynamic (PD) changes in xenograft tissue, tumor growth inhibition (TGI), and mouse body weight (BW) was evaluated across a range of doses. SY-5609 TGI activity was also evaluated at sub-maximum-tolerated-dose levels across a panel of 30 independent CRC models including BRAF-, KRAS-, and non-BRAF/KRAS-mutant (wild type) models (n = 10 per group). Results: SY-5609 induced dose-dependent TGI in BRAF-mutant CRC PDX tumors, with tumor regressions observed at well tolerated doses (no BW loss at EOT), and no tumor regrowth for 2+ weeks after treatment was discontinued. Dose-dependent TGI was associated with dose-dependent PD changes in PDX tumor tissue. Across 30 PDX models, SY-5609 at well-tolerated doses (average BW loss of 0% at EOT across all models) induced ≥50% TGI in 67% (20/30) of models. Deep responses (≥90% TGI or regressions) were observed in 23% (7/30) of models, with enrichment for deep responses in BRAF mutant models (50%, 5/10) relative to KRAS mutant (10%, 1/10), and wild type (10%, 1/10) models. Conclusions: Daily oral dosing of the CDK7 inhibitor SY-5609 induces robust TGI, including regressions, in CRC PDX models at well-tolerated doses. Dose-dependent TGI is associated with dose-dependent PD changes in CRC PDX tumor tissue. These results highlight the therapeutic potential of SY-5609 in CRC and support the evaluation of SY-5609 in CRC patients in early phase clinical trials. SY-5609 is in phase 1 clinical development for patients with advanced solid tumors including CRC (NCT04247126).