Problem

Despite recent progress in cancer therapy, acquired resistance to existing cancer drugs reduces therapeutic efficacy. There is a strong need for a therapy with a novel mode of action to overcome drug resistance, and to improve therapeutic efficacy whether used alone or in combination therapy.

Solution

• Researchers from The Ohio State University have developed a series of novel pyrrolopyrimidine derivatives and obtained potent reversible ATP-competitive inhibitors to Mps1/TTK (threonine tyrosine kinase). Inhibition of Mps1/TTK enables progression to anaphase without proper chromosome segregation, resulting in DNA damage and micronuclei formation, which leads to cytoplasmic dsRNA and dsDNA that triggers a DNA-driven immune response via activation of the STING and MAVS pathway in cancer cells, eliciting an anti-tumor immune response
• Lead characterization has shown that the lead compound (OSU-13 series) has the property of best-in-class small molecule drug candidate

• OSU TTK inhibitors retain full potency against BRAFV600E melanoma cell lines with acquired resistance to BRAF V600E inhibitors
• OSU311 in combination with trametinib impairs tumor growth in a BRAF V600E A375 melanoma xenograft
• OSU201 provides monotherapy benefits and synergizes with anti-PD-1 in an aggressive syngeneic colorectal cancer model

Applications

• Cancer therapy for solid cancer: melanoma, colorectal cancer, pancreatic cancer, glioblastoma multiforme
• Combination therapy: TTK inhibition synergizes with MEK inhibitors and/or immune checkpoint inhibitors

Advantages

• Highly selective for TTK: 0 of 370 other kinases inhibited at 100 nM
• Potent: Biochemical IC50 < 4 nM, Cellular EC50, 11 nM
• Favorable DMPK
• >50% orally bioavailability
• Brain penetrant: 0.3 – 2.6 brain to plasma ratio
• Effective as a single agent and in combination therapy. Synergize with BRAF/MEK inhibitors and immune checkpoint inhibitors
• Effective against BRAFi/MEKi resistant cancers

Seeking opportunities for co-development, out-licensing or new venture formation