QuEEN:

The crown of

drug discovery

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.

MRT-6160 is a potent, highly selective, and orally bioavailable investigational molecular glue degrader of VAV1, which in our in vitro studies has shown deep degradation of its target with no detectable effects on other proteins. VAV1, a Rho-family guanine nucleotide exchange factor, is a key signaling protein downstream of both the T- and B-cell receptors. VAV1 expression is restricted to blood and immune cells, including T and B cells. Preclinical studies have shown that targeted degradation of VAV1 protein via an MGD modulates both T- and B-cell receptor-mediated activity. This modulation is evident both in vitro and in vivo, demonstrated by a significant decrease in cytokine secretion, proteins vital for maintaining autoimmune diseases. Moreover, VAV1-directed MGDs have shown promising activity in preclinical models of autoimmune diseases and thus have the potential to provide therapeutic benefits in multiple systemic and neurological autoimmune indications, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and dermatological disorders. Preclinical studies demonstrate MRT-6160 inhibits disease progression in in vivo autoimmunity models.

MRT-8102 is a potent, highly selective, and orally bioavailable investigational molecular glue degrader (MGD) that targets NEK7 for the treatment of inflammatory diseases driven by IL-1b and the NLRP3 inflammasome. NEK7 has been shown to be required for NLRP3 inflammasome assembly, activation and IL-1b release both in vitro and in vivo. Aberrant NLRP3 inflammasome activation and the subsequent release of active IL-1b and interleukin-18 (IL-18) has been implicated in multiple inflammatory disorders, including gout, cardiovascular disease, neurologic disorders including Parkinson’s disease and Alzheimer’s disease, ocular disease, diabetes, obesity, and liver disease. In a non-human primate model, MRT-8102 potently, selectively, and durably degrades NEK7 and results in near-complete reductions of IL-1b models following ex vivo stimulation of whole blood. MRT-8102 has shown a favorable profile in non-GLP toxicology studies.

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 promoted the association of CDK2 and cereblon in vitro, while avoiding other CDKs, and are in the process of optimizing the chemical leads.

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.