REC-1245

Solid tumors and lymphoma

Status:

Phase 1

Population:

>100,000*

REC-1245 is a highly potent RBM39 degrader being developed for the treatment of solid tumor indications and lymphoma, with multiple biomarkers being explored. RBM39 was identified using phenotypic insights by the Recursion OS, and is a novel target mimicking CDK12 loss. There are currently no RBM39 degraders approved by the FDA. Early preclinical data shows REC-1245 reduces viability in tumors characterized by replication stress and DNA repair vulnerabilities (DDR defects) across multiple solid tumor types, including MSI-H/dMMR, HRR altered cancers, and other tumors.

Learn more on clinicaltrials.gov

*Addressable incidence with biomarker-enriched solid tumors and other select histologies. All populations defined above are US and EU5 incidence unless otherwise noted. EU5 is defined as France, Germany, Italy, Spain, and UK.

Case study

REC-1245: An AI-enabled RBM39 Degrader Optimized to Potentially Bypass Class-limiting CDK12/13 Toxicity

The challenge:

Finding a New Path to a Historically Intractable Target

There are many potential high-interest cancer targets that have proven historically difficult to drug. Finding a way to access these targets could provide novel and differentiated treatment options for patients.

One example is cyclin-dependent kinase 12 (CDK12) - a well-characterized cancer target involved in DNA damage repair (DDR) pathways, which has been previously hard to target due to safety issues. CDK12 has a highly similar structure and function to CDK13. Traditional CDK12 inhibitors have also affected CDK13, which leads to severe adverse effects in normal tissues. There’s an unmet need for an alternative approach that captures the therapeutic benefit of CDK12 inhibition without the resulting off-target CDK13 toxicity.

Our Map of Biology showed that there was a high degree of phenotypic similarity between CDK12, RBM39, and multiple concentrations of REC-1245 but that CDK13 shows little or no functional similarity to CDK12, RBM39, or any concentration of REC-1245.

The unique how:

Map-Based Inference & Accelerated Molecular Glue Design

We can now leverage technologies such as AI to gain a more holistic understanding of the underlying biology, leading to new targets and treatment strategies. We leveraged our Maps of Biology – which predict the functional relationships of every gene across the genome – to explore novel targets. From this, we discovered a completely novel biological relationship: that the genetic knockout of the RNA-binding motif protein 39 (RBM39) phenotypically and selectively mimics CDK12 loss without impacting CDK13.

This unbiased biological insight suggested targeting RBM39 could potentially achieve the same therapeutic effect as targeting CDK12. Recursion used its phenomics-based platform for chemical optimization to design REC-1245, a novel RBM39 molecular glue degrader. REC-1245 was designed and synthesized in only 204 compounds, advancing from target identification to IND-enabling studies in only 18 months—more than twice the speed of the industry average.

The outcome:

A Potential First-in-Class, Biomarker-Driven Profile

REC-1245 is a novel, potent, and selective molecular glue degrader of RBM39 designed to overcome the limitations of direct CDK12 inhibition:

REC‑1245 induces significant tumor regressions in an ovarian CDX model which is driven by elevated replication stress

Emerging preclinical data show that replication stress is a potential signature for REC-1245 sensitivity, suggesting that REC-1245 treatment could be used to target tumors characterized by drivers of genomic instability

Potential Improved Safety and Selectivity: REC-1245 inhibits the DNA damage repair (DDR) pathway and induces cell cycle arrest by targeting RBM39, bypassing CDK12 inhibition and completely avoiding toxic CDK13 off-target effects. It also has minimal ITGA2 liability, an off-target issue seen with previous RBM39 degraders.
Compelling Preclinical Efficacy: REC-1245 drives strong, dose-dependent anti-tumor activity, including tumor regression in an ovarian cancer BRCA-proficient, p53 mutant cancer model.
Precision Patient Stratification: Finding the right patients to treat with REC-1245 is also important for positive clinical outcomes. Emerging preclinical data has identified that REC-1245 could be used to target tumors characterized by drivers of genomic instability, such as tumors characterized by replication stress and DNA repair vulnerabilities (DDR defects). This could provide a potential signature for REC-1245 sensitivity, creating a biomarker-based strategy for our clinical trial, to include the patients potentially most likely to respond.

Learn more about clinical trial at Recursion.

Clinical trials

The why:

Delivering Precision Oncology to Genomically Unstable Cancers

REC-1245 aims to provide a safer, first-in-class treatment option for >100,000 addressable patients annually in the US and EU5 who have specific advanced solid tumors and lymphoma. By identifying a potential signature for REC-1245 sensitivity, this program moves away from a "one-size-fits-all" approach to potentially deliver precision oncology treatments for patients whose aggressive cancers rely on DNA repair vulnerabilities. REC-1245 is currently under investigation in the open-label Phase 1/2 DAHLIA trial. Neither its safety nor efficacy is established.

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