Sporos BioDiscovery
Sporos BioDiscovery is a wholly owned portfolio of Sporos Bioventures. Sporos BioDiscovery is developing small molecule precision oncology candidates, including its lead asset SPR1, a pre-clinical TEAD inhibitor.
The Hippo Pathway & TEAD
The Hippo pathway is a major regulator of cell number and tissue density. It plays a key role during embryogenesis, and modulates genes responsible for proliferation, differentiation, organ growth, as well as tissue homeostasis.
TEAD is a family of four transcription factors that execute the Hippo pathway. These four TEAD paralogs have both redundant and distinctive functions, some of which have pro-proliferative effects on cancer and some of which have anti-proliferative effects.
Mutations in the Hippo pathway can cause activation of YAP/TAZ –TEAD transcription and are associated with the hallmarks of oncology.
Through significant bioinformatic analysis, we have identified TEAD1 and TEAD4 as the most critical paralogs to inhibit to maximize anti-tumor activity and minimize toxicity.
SPR1
Through significant bioinformatic analysis, we have identified TEAD1 and TEAD4 as the most critical paralogs to inhibit to maximize anti-tumor activity and minimize toxicity.
SPR1 is a first-in-class TEAD1 and TEAD4 inhibitor, which has demonstrated improved single agent preclinical activity, both in vivo and in vitro, compared to other TEAD inhibitors in development, particularly those targeting primarily TEAD1.
SPR1’s unique TEAD1 / TEAD4 selectivity profile has demonstrated broader preclinical activity than other TEAD inhibitors in development across many cancer cell lines that harbor Hippo pathway aberrations. Cancers such as mesotheliomas, of which over 80% harbor a Hippo pathway mutation, and squamous cell carcinomas of the lung, head and neck are all cancers that commonly have Hippo mutations.
In addition to broader preclinical activity in Hippo-mutated cancers, SPR1 has demonstrated strong activity in cancer cell lines where YAP is shown to be hyperactive in the nucleus of cancer cells; however, no Hippo aberrations have been detected. This points to the broad potential for SPR1 as monotherapy across a wide array of cancers that current TEAD inhibitors in development are so far unable to address.
The Hippo and MAPK Pathways
With the MAPK pathway sharing a number of overlapping proliferation, self-renewal, survival, and immune genes, Hippo pathway activation has emerged as a key mechanism of resistance to inhibitors of the MAPK pathway.
Combination therapy of TEAD inhibitors with MAPK pathway drugs offer opportunity for greater efficacy. To date, SPR1 has demonstrated strong synergy with drugs targeting the MAPK pathway and its upstream components, such as KRAS, MEK, EGFR, and FGFR inhibitors.
For this reason, Sporos BioDiscovery is focused on optimizing the inhibitory profile across these four TEADs is to create a best-in-class therapeutic candidate.
