zemirciclib (AZD4573)

Relapsed/refractory (R/R) disease is a major hurdle to long-term survival of acute myeloid leukemia (AML) patients treated with intensive cytarabine (AraC)-based chemotherapy. The roles of MCL-1 and c-MYC in the three-drug combination were confirmed by knockdown. This study demonstrates that AZD4573 enhances the activity of VEN + AZA against AraC-resistant AML by downregulating c-MYC and MCL-1 and to a lesser extent cellular respiration.

CDK9 inhibitors show promising activity against patient-derived models of CRC. MAPK signaling is particularly suppressed by CDK9 inhibitors. Combining CDK9 inhibitors and targeted therapy against MAPK signaling pathway may be a viable strategy worthy of further investigation preclinically and clinically.

Inhibition of CDK9 by AZD4573 induces the accumulation of DNA damage through T-R conflicts. DDX25 helicases were identified as a key mediator in resolving T-R conflicts and the reduced sensitivity to AZD4573.

We also showed that targeting CDK9 by AZD4573 and enitociclib is a safe and effective treatment in preclinical MCL models, supporting CDK9 as a valid therapeutic target for MCL. Furthermore, YX0798 has the potential to be used in combination therapy with clinical agents to improve treatment efficacy. Together, these data demonstrate that YX0798 has oral bioavailability, exquisite selectivity, and anti-tumor potency that results from driving transcription reprogramming towards tumor cell killing.

We selected thyroid cancer cell lines with a variety of genetic drivers for initial screening studies with CDK7/12/13 (THZ1) and CDK9 (AZD4573) inhibitors...Combined reduction in CDK12/13 levels with siRNA reduced RNAPII phosphorylation. These data suggest that specific inhibitors of CDK12/13 may be particularly active in thyroid cancer cell lines; further studies evaluating their efficacy are warranted in thyroid cancer.

P1/2, N=40, Completed, AstraZeneca | Active, not recruiting --> Completed

In vitro application of the CDK9 inhibitor AZD4573 and XPO1 inhibitor Selinexor significantly reduced DLBCL cell line viability as single agents and produced synergistic results when applied in combination. Our analysis presents key associations between the MYC oncogene and depleted TME presence capable of providing clarity within the evolving precision CAR-T treatment landscape.

CDK9 inhibitors AZD4573 and atuveciclib reduced the IFN-γ induced PD-L1 expression in a dose-dependent manner. In conclusion, CDK9 inhibition could reduce the expression of PD-L1 in HCC cells. Using both CDK9 inhibitors and anti-PD-L1 antibodies is more effective than using either agent alone.

P2, N=52, Completed, AstraZeneca | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Feb 2024

P1/2, N=40, Active, not recruiting, AstraZeneca | Trial completion date: Sep 2023 --> Dec 2024

P2, N=52, Active, not recruiting, AstraZeneca | N=81 --> 52 | Trial completion date: Aug 2024 --> Dec 2024

Current standard of care for pTCL revolves around the chemotherapy regimens CHOP/E and for CD30-postive pTCLs, brentuximab vedotin is approved...Using the MCL-1 inhibitor AZD5991, we have shown statistically significant benefit in survival when combined with CHOP in 2 MCL-1 dependent preclinical pTCL PDX models (Koch et al...These data suggested that treatment with AD4573 either as a monotherapy or in combination with CHOP, would be an effective therapeutic strategy in pTCL. AZD4573 monotherapy is currently being evaluated in a phase 2 study (NCT05140382) to assess the efficacy, safety, and PK in patients with relapsed/refractory pTCL.