Our Pipeline
Zentalis develops small molecule therapeutics with differentiated product profiles for a broad range of cancers.
Compound
Indication + Development Approach
Preclinical
Phase 1
Phase 1b
Phase 2
Phase 3
Azenosertib WEE1 Inhibitor
ZN-d5 BCL-2 Inhibitor
BCL-xL Degrader
Product Candidates
Azenosertib WEE1 Inhibitor
Azenosertib is a potentially first-in-class and best-in-class small molecule Wee1 inhibitor in development for the treatment of cancer. Inhibition of WEE1, a DNA damage response kinase, drives cancer cells into mitosis without being able to repair damaged DNA, resulting in cell death. Currently, there are no FDA-approved WEE1 inhibitors, and we have designed Azenosertib to have advantages over other investigational therapies, including superior selectivity and pharmacokinetic properties.
Azenosertib is being developed in three therapeutic settings of high unmet need:
- WEE1 is a protein kinase that inhibits the activity of both CDK1 and CDK2 kinases and is involved in the regulation of G1/S, G2/M, and M phase cell cycle checkpoints
- WEE1 plays an important role during normal cell cycle progression but also in response to DNA damage and interacts with DNA damage response (DDR) pathways
- WEE1 inhibition causes cancer cells to proceed into mitosis without being able to repair damaged DNA, resulting in prematuremitotic entry andapoptosis
- WEE1 inhibition also increases replication stress by inducing aberrant firing of replication origins and depletion of nucleotide pools
- WEE1 plays a crucial role in cell cycle regulation and DNA damage response (DDR) in both non-malignant and cancer cells
- WEE1 phosphorylates CDK1 and CDK2 and negatively regulates CDK/ Cyclin complexes to inactivate them
- Inactive Cyclin/CDK complexes permit cell cycle arrest at checkpoints, allowing cells to repair DNA damage before mitosis
- Cells with functioning WEE1 can repair their DNA adequately and effectively proliferate
- When WEE1 is inhibited by azenosertib in cancer cells, Cyclin/CDK complexes remain unphosphorylated and activated
- Active Cyclin/CDK complexes allow the cell cycle to progress without repairing DNA damage
- Azenosertib causes cancer cells to accumulate DNA damage, resulting in replication stress, mitotic catastrophe and apoptosis
- CCNE1 gene amplification is a common oncogenic driver in many solid tumors, including high grade serous ovarian carcinomas
- Both CCNE1 gene amplification and high Cyclin E1 protein expression have been associated with chemotherapy resistance and poor patient outcomes1
- Cyclin E1 overexpression, which can also occur in the absence of CCNE1 gene amplification, increases CDK2 activity and accelerates G1/S transition2
- Cyclin E1 overexpression results in replication stress and renders cells more dependent on the WEE1 G2/M cell cycle checkpoint 2
ZN-d5 BCL-2 Inhibitor
ZN-d5 is a selective, oral small molecule inhibitor of B-cell lymphoma 2 (BCL-2), which is currently being evaluated in patients with hematologic malignancies. BCL-2 is a protein that plays a critical role in the regulation of cell death, known as apoptosis. The overexpression of BCL-2 is frequently detected in numerous cancer types, which prevents apoptosis of cancer cells. Utilizing our medicinal chemistry expertise, we have designed ZN-d5 to have best in class potency, selectivity and pharmacokinetic properties.
ZN-d5 is being studied in both monotherapy and combination settings:
- Phase 1/2 Study of Monotherapy in Relapsed or Refractory Light Chain (AL) Amyloidosis
- Phase 1 Study of Monotherapy in Non-Hodgkin’s Lymphoma (NHL)
- Phase 1/2 Study in Combination with Azenosertib in Relapsed or Refractory Acute Myeloid Leukemia (AML)
BCL-xL Degrader
BCL-xL is a member of the anti-apoptotic BCL-2 proteins. Its overexpression in tumor cells contributes to tumor survival and therapeutic resistance mechanisms. Our protein degrader candidate is designed to have better efficacy and tolerability over other clinical-stage BCL-xL targeted inhibitors and has demonstrated potent anti-cancer activity in several preclinical models.