Developing a RPN13 inhibitor for the treatment of Quadruple Negative Breast Cancer

Quadruple negative breast cancer (QNBC), lacking the expression of ER (estrogen receptor), PR
(progesterone receptor), HER2 (human epidermal growth factor receptor 2) and AR (androgen receptor), is the
breast cancer subtype with the worst prognosis, and QNBC disproportionately afflicts African
Americans. It has no standard-of-care treatment targets and thus efficacious and safe treatments must be
urgently sought for this unmet medical need, and to address the disparity in breast cancer outcomes.
The current proposal is motivated by data showing elevated expression of proteasome subunit RPN13 is
associated with both African American race and lower survival in QNBC patients, that RPN13 targeted by our
Up284 inhibitor, a strong ongoing collaboration with Dr. Karanam (TU), and the guidance of Dr. Yates (TU) in
health disparity research and Dr. Davis (Weill Cornell) in breast cancer subtypes. Both triple negative breast
cancer and QNBC cell lines show evidence of greater vulnerability to proteasome inhibitors. However, licensed
20S proteasome inhibitors, e.g. bortezomib, have proven ineffective against solid tumors, with emergence of
resistance, and dose limiting toxicities including thrombocytopenia and neutropenia. Up284 has a target and
structure designed to overcome the limitations of the licensed drugs with respect to drug resistance (Up284
blocks substrate recognition and deubiquitination rather than just one of the three 20S catalytic
activities), poor activity against solid tumors (Up284 has a novel spiro structure with evidence of
improved drug access to tumor as compared to peptide-based 20S inhibitors), key toxicities of
thrombocytopenia and neutropenia (unlike 20S inhibitors, Up284 does not target the immunoproteasome
expressed by hematopoietic cells and does not show these toxicities). Up284 shows broad anticancer
activity in vitro, including against QNBC lines with a robust therapeutic index, a promising safety profile and
pharmacodynamics, and the ability to control xenograft tumor. This promising data reflects our extensive
medicinal chemistry effort to achieve drug-like properties and a patent has been filed globally to cover the
novel backbone and lead compounds. By inhibiting proteasome ubiquitin receptor RPN13 function and its
associated deubiquitinase activity, Up284 triggers more rapid accumulation and increased molecular weight
polyubiquinated protein aggregates than is induced by 20S inhibitors. These toxic misfolded protein
aggregates produce an unresolved ER stress, activate the canonical Unfolded Protein Response (UPR)
signaling cascade and more rapidly triggers apoptosis than 20S inhibitor. The safety parameters and promising
efficacy of Up284 against breast cancer lines encourages us to validate Up284 efficacy in more QNBC lines
and xenografts, and examine key mechanistic and drug pharmacologic questions. This proposal will address
questions critical for the development of QNBC as the lead indication for our iRPN13, Up284, and to support a
pre-IND application to FDA.Quadruple Negative Breast Cancer (QNBC) is a particularly aggressive form of breast cancer that
disproportionately afflicts African Americans. Although the licensed peptide-based proteasome inhibitors are
effective against multiple myeloma, unfortunately they have not proven useful to treat solid tumors (e.g. QNBC).
Up Therapeutics is developing a novel drug with a structure designed to improve uptake into solid tumor, and
targeting a different component of the proteasome (RPN13), as candidates to better treat QNBC.