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 ZN-c3 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:

1. As a monotherapy

• Phase 2 Monotherapy Study in Uterine Serous Carcinoma
• Phase 1 Monotherapy Dose Optimization Study in Solid Tumors
• Phase 1/2 Monotherapy Study in Cyclin E1 Driven High Grade Serous Ovarian Cancer

2. In combination with traditional chemotherapy and DNA damaging agents

• Phase 1b Combination Study of Azenosertib and PARPi in PARP Resistant Ovarian Cancer
• Phase 1/2 Combination Study of Azenosertib and Chemotherapy in Ovarian Cancer
• Phase 1/2 Combination Study of Azenosertib and Gemcitabine in Osteosarcoma

3. In combination with molecularly targeted agents

The Company has announced it will collaborate with Pfizer on a Phase 1/2 dose escalation study of azenosertib in combination with encorafenib and cetuximab in patients with BRAF V600E-mutated colorectal cancer. The Company initiated enrollment in this clinical trial in the first quarter of 2023.

Normal State

• 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

• 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

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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 Relapsed or Refractory Acute Myeloid Leukemia (AML) and Non-Hodgkin’s Lymphoma (NHL)
• Phase 1/2 Study in Combination with Azenosertib in Relapsed or Refractory Acute Myeloid Leukemia (AML)

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.