GLB-001, China’s First Selective CK1α Molecular Glue Protein Degrader, Approved for Clinical Trials

February 20, 2024

San Diego, California, Feb 19, 2024 - GluBio Therapeutics Inc., a clinical-stage, Molecular glue degrader (MGD)-focused biotech company, announced that GLB-001, an independently developed, orally available molecular glue protein degrader targeting Casein Kinase 1α (CK1α) with global intellectual property rights and "first-in-class" potential, has received the drug clinical trial approval from the National Medical Products Administration (NMPA) to initiate clinical trials of GLB-001 in myeloid malignancies.

GLB-001 is the first CK1α-selective molecular glue degrader to enter the clinical development stage in China, marking another significant breakthrough for domestic companies in the field of targeted protein degradation drug discovery. In 2023, GLB-001 had already received approval from the U.S. Food and Drug Administration (FDA) to proceed with clinical trials for the treatment of relapsed/refractory acute myeloid leukemia (R/R AML) or relapsed/refractory higher-risk myelodysplastic syndromes (R/R HR-MDS). Patient recruitment is currently ongoing.

Based on the preclinical pharmacological and toxicological data for GLB-001, as well as its safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy data in patients with R/R HR-MDS and R/R AML, GluBio Therapeutics plans to leverage existing clinical strengths in China over the next 2-3 years to further investigate the efficacy of GLB-001 across various related myeloid malignancy indications. This effort aims to fully explore the potential clinical value of GLB-001 and better address the needs of patients with different indications.

“Including GLB-001, we now have two novel molecular glue protein degraders in the clinic, targeting myeloid malignancies and lymphoma, respectively.“ said Gang Lu, Ph.D., Founder, President and CEO of GluBio Therapeutics. “GLB-001 has already initiated patient enrollment for its Phase I clinical trial in the United States. This approval for clinical trials in China will further accelerate the global clinical development program for this asset. We will actively maintain communication with regulatory agencies in both China and the U.S., flexibly utilize clinical data from both regions to expedite the clinical trial progress, and strive for the earliest possible approval and market availability of GLB-001, aiming to address the significant unmet medical needs in the treatment of hematological tumors to the greatest extent.”

About CK1α-selective Molecular Glue Degrader

CK1α, a serine/threonine protein kinase encoded by the CSNK1A1 gene, has been demonstrated to be crucial for the growth and survival of many different types of hematological malignancies and solid tumors. By directly regulating several major signaling pathways, including the tumor protein 53 (p53), Wnt/β-catenin, and nuclear factor kappa-B (NF-κB) pathways, CK1α plays a key role in modulating cellular homeostasis¹. Lenalidomide is a multi-targeted, non-selective molecular glue protein degrader. It functions by binding to the substrate receptor cereblon (CRBN) within the CUL4–DDB1–CRBN–RBX1 (CRL4^CRBN) E3 ubiquitin ligase complex, leading to the targeted degradation of CK1α, as well as other CRBN neosubstrates including Ikaros family zinc finger protein 1 (IKZF1), Ikaros family zinc finger protein 3 (IKZF3), and zinc finger protein 91 (ZFP91) ^2-4. Besides its proven efficacy in multiple myeloma (MM) and lower-risk myelodysplastic syndromes with del(5q), lenalidomide has also shown clinical activity as a monotherapy or in combination with standard agents in certain off-label contexts, including patients with AML and chronic myeloid leukemia (CML)⁵. Published research as well as our internal preclinical data suggested that lenalidomide, as a weaker and less selective CK1α molecular glue degrader, shows a correlation between the extent of induced CK1α degradation and its efficacy in AML and MDS cell lines. Therefore, the limited clinical activity observed with lenalidomide in off-label patient populations may be attributed to insufficient degradation of CK1α in tumor cells, as well as treatment interruptions caused by off-target toxicities associated with the degradation of IKZF1 (another novel substrate of lenalidomide)⁶.

About GLB-001

GLB-001 is an oral potent and highly selective casein kinase 1 alpha (CK1α) molecular glue degrader, which coopts the CRL4^CRBN E3 ubiquitin ligase complex to target CK1α for polyubiquitination and subsequent proteasomal degradation with much improved degradation potency and selectivity for CK1α when compared to lenalidomide. Mechanistically, GLB-001-induced CK1α degradation triggers the activation of p53 signaling, resulting in cell cycle arrest and apoptosis of leukemic cells.

Preclinical data from GluBio demonstrated that GLB-001 exhibits robust in vitro and in vivo anti-tumor activity, along with a favorable safety and tolerability profile. GLB-001 monotherapy shows remarkable anti-tumor efficacy in multiple xenograft models. Furthermore, GLB-001 shows substantial improvement in both CK1α degradation potency and selectivity compared to lenalidomide, the non-selective CK1α molecular glue degrader. It holds promise as a potential treatment option for patients with advanced tumors, particularly those with myeloid hematological malignancies.

About Myeloid Malignancies

Myeloid malignancies are hematologic cancers resulting from the abnormal proliferation of hematopoietic stem cells. They include Acute Myeloid Leukemia (AML), Myelodysplastic Syndromes (MDS), and Myeloproliferative Neoplasms (MPN). Clinically, they represent a highly heterogeneous group of hematopoietic system diseases that are difficult to cure and are associated with poor prognoses, with a globally increasing incidence in recent years. Currently, treatment options for myeloid malignancies are very limited. Allogeneic hematopoietic stem cell transplantation is currently the only potentially curative approach, but the majority of patients lack this opportunity. For patients receiving other standard treatments, such as chemotherapy or targeted therapy, are highly prone to relapse or to develop drug resistance, representing a major clinical challenge in the management of myeloid malignancies. Therefore, there remains a significant unmet medical need for the treatment of myeloid malignancies, underscoring the urgent demand for new therapeutic options.

Reference

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