Pipeline

MRT-2359 is a potent, selective, and orally bioavailable molecular glue degrader (MGD) that induces the interaction between the E3 ubiquitin ligase component cereblon (CRBN) and the translation termination factor GSPT1, leading to the targeted degradation of GSPT1 protein. The MYC transcription factors (c‑MYC, L-MYC, and N-MYC) are well-established drivers of human cancers that maintain high levels of protein translation, which is critical for uncontrolled cell proliferation and tumor growth. Our preclinical studies have shown that this addiction to MYC-induced protein translation creates a dependency on GSPT1. MRT-2359 exploits this vulnerability by inducing degradation of GSPT1, disrupting protein synthesis preferentially in MYC-driven cell lines and leading to anti-tumor activity in MYC-driven tumor models. A phase 1/2 clinical study aims to evaluate the safety, tolerability, and anti-tumor activity of MRT-2359. Details about our study of “Oral MRT-2359 in Selected Cancer Patients” can be found at ClinicalTrials.gov under identifier: NCT05546268.

Cyclin dependent kinases, or CDKs, are a family of closely related kinases that regulate progression through the cell cycle. CDK activity is further modulated by levels of specific cyclins, for example, cyclin E1 activates cyclin-dependent kinase 2, or CDK2. Tumors with CDK2 are activated by (i) the amplification of Cyclin E1 or E2 or the loss of the AMBRA1 gene and (ii) the loss of retinoblastoma. Cyclin E1 dysregulation has been found in a number of cancers, including ovarian and triple negative breast cancer. In addition, cyclin E1 dysregulation and CDK2 activation has also been found to be one of the mechanisms of resistance in estrogen receptor positive breast cancer patients treated with CDK4/CDK6 inhibitors, such as palbociclib. Therefore, we believe selective elimination of CDK2 may provide benefit to these patients. Small molecule inhibitors and PROTACs of CDK2 have been limited in their selectivity due to the high degree of similarity among the active sites of CDKs. We have identified multiple MGD molecules that selectively degrade CDK2 while avoiding other proteins, including CDKs.

Cyclin proteins play crucial roles in regulating cell cycle progression by binding and activating cyclin-dependent kinases (CDK). Cyclin E1 protein, encoded by CCNE1, is an essential regulator of G1-to-S transition, and is also critical for DNA replication initiation. Cyclin E1 is a principal oncogenic driver, amplified in multiple cancers, including ovarian, endometrial, gastric and breast, and its expression in tumor cells is associated with poor prognosis. Therefore, in these areas of significant unmet medical need, selective elimination of cyclin E1 is expected to provide vital benefit to patients with aggressive malignancies. Once considered an “undruggable” cancer target by conventional small molecule inhibitor approaches, we have identified multiple MGD molecules that selectively degrade cyclin E1, and are in the process of optimizing the chemical leads. Cyclin E1 degrader represents a unique opportunity to expand the druggable target space and transform lives and outcomes for patients with devastating diseases.