Small Molecule CUL4 Inhibitors as Dual Precision Oncology and Immuno-Oncology Drugs

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Culnexin Therapeutics LLC is a startup biotechnology company developing first-in-class small molecule drugs that inhibit the CUL4A ubiquitin ligase as a treatment for triple negative breast cancer (TNBC). Breast cancer is the second leading cause of death for women, with 1 in 8 women diagnosed within her lifetime. TNBC comprises approximately 10-15% of the 323K new cases annually, disproportionately affects younger women, and is a more aggressive disease for which no effective/targeted treatments exist. The goal of this STTR is to address the lack of targeted treatment for patients with TNBC by developing small molecule CUL4A inhibitors. Culnexin founder Dr. Pengbo Zhou at Weill Cornell Medicine discovered that CUL4A overexpression (CUL4Ahigh) drives multiple cancer types and is a poor prognostic indicator of patient survival. CUL4Ahigh TNBCs are addicted to high levels of CUL4A expression, and genetic inactivation of CUL4A leads to selective killing of CUL4Ahigh tumors while leaving healthy tissue unaffected. Importantly, CUL4A inactivation also causes massive infiltration of cytotoxic T and NK cells into tumors, making CUL4A a unique target for both targeted intervention and immuno-oncological therapy. We have conducted a high throughput screen of 240,000 compounds and identified/validated multiple hit compounds capable of selective CUL4A inhibition. Structure- activity relationship (SAR) analysis led to the generation of early lead compounds that displayed low nanomolar affinity and exquisite anti-TNBC activities in vitro and in vivo. The long-term goal of Culnexin is to improve outcomes for patients with TNBC by providing them with a mechanistically novel, dual-action cancer therapy. In this phase I STTR Administrative Supplement, we will develop PA9 analog CUL4A inhibitors more effective than our current compounds. We will (1) carry out structure-function analysis to obtain a panel of lead PA9 analogs for CUL4A inhibition; (2) determine the in vivo DMPK/ADMETox properties and anti-tumor efficacies of lead CUL4A inhibitors in clinically relevant models of TNBC. This work will develop more drug-like CUL4A inhibitors and validate them in appropriate TNBC models. In Phase II, we will generate advanced preclinical data in order to submit an Investigational New Drug (IND) application to the FDA. Our anti-CUL4A drugs represent a first-in-class treatment for the 47% of TNBC patients with CUL4Ahigh tumors diagnosed each year. We anticipate our drug will qualify for Fast Track under FDA rules due to the highly novel mechanism of action and unmet need. We plan to bring our product to market by partnering with large pharma during phase II STTR studies.