Our Science
Long-Acting Radionuclide-Drug Conjugates
Targeting tumors with radioligands
The use of radiation in medicine dates back to late 19th century when X-ray was first discovered, and is now extensively used. Radioligand therapy (RLT) is an emerging therapy to treat cancer with radiation. Unlike conventional radiation therapy, RLT targets and delivers cytotoxic radiation to cancer cells, producing direct tumoricidal effects with minimal toxicity on healthy cells.
Typically, therapeutic radioligands consist of three parts: a cell-killing radionuclide (often attached on a chelator), a tumor-targeting vehicle and a linker connecting these two parts.
Currently, radioligands have been used for the treatment of a variety of cancers, including thyroid carcinoma (131I-MIBG, approved), neuroendocrine tumors (177Lu-DOTATATE, approved), castration-resistant prostate cancers (177Lu-PSMA-617, approved) and bone metastases (223RaCl2, approved).
Improving tumor retention of radiolabeled small-molecules by albumin binders
Radiolabeled small molecules or antibodies are commonly used in RLT. Since small molecules are about 100-fold smaller that antibodies, they are capable of crossing blood vessels to penetrate into tumors, but also being eliminated rapidly by kidney. Therefore, radiolabeled small-molecules potentially lack efficacy due to shorter tumor retention time.
The incorporation of a reversible albumin binding moiety to small-molecules is one of the common strategies to increase the circulation time and subsequently, the efficacy. Such strategy has been successfully applied in GLP-1 analogues, such as Albiglutide and Semaglutide, which require weekly administration for the treatment of type-2 diabetes. Similarly, radiolabeled small-molecules with an albumin-binding moiety are capable of increasing their half-life and tumor uptake. For example, 177Lu-EB-PSMA-617 is a radioligand with Evans blue (EB) as its albumin-binding moiety. In a phase 1 study, 177Lu-EB-PSMA-617 showed 2.15-5.68-fold higher tumor accumulation than the conventional 177Lu-PSMA-617.
ScinnoHub is developing radiolabeled small-molecules
with albumin binding moieties in order to prolong their
in vivo circulation and clinical efficacy
with albumin binding moieties in order to prolong their
in vivo circulation and clinical efficacy
References
1. Radiopharmaceuticals: Radiation Therapy Enters the Molecular Age.
2. Radionuclide therapy. https://www.iaea.org/topics/radionuclide-therapy.
3. Zang J, Liu Q, et al. 177Lu-EB-PSMA Radioligand Therapy with Escalating Doses in Patients with Metastatic Castration-Resistant Prostate Cancer. J Nucl Med. 2020;61(12):1772-1778.
4. Lau J, Bloch P, et al. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem. 2015;58(18):7370-80.
5. Sgouros G, Bodei L, McDevitt MR, Nedrow JR. Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov. 2020;19(9):589-608.
6. Zang J, Fan X, et al. First-in-human study of 177Lu-EB-PSMA-617 in patients with metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2019;46(1):148-158.
Drug Screening for RNA Splicing Modulator
RNA splicing modifier is an emerging concept extending drug discovery beyond conventional protein-based R&D
Eukaryotic genes consist of multiple exons (coding sequences) interspersed with introns that undergo RNA splicing to join exons and form mature mRNA. In addition, various mRNAs are generated from a single gene by arranging exons into different combinations in a process called alternative splicing. It has been known that alternative splicing not only contributes to diverse proteome, but also promotes pathological conditions, such as certain cancers and rare diseases.
RNA splicing is regulated by both trans-acting factors and cis-acting regulatory elements. The trans-acting factors, including large spliceosome complex, interact with cis-acting regulatory elements to maintain correct exon recognition and splicing outcome. Therefore, mutations in trans-acting regulatory proteins and cis-acting regulatory elements give rise to various pathological conditions. For example, mutations in MET gene cause exon-skipping and generate MET gene lacking exon 14 (METexon14△). Since a key residue in exon 14 is critical for ubiquitin-mediated MET degradation, METexon14△ promotes proliferation of lung adenocarcinomas. In addition, decades of studies have shed light on the pathological alternative splicing as the causative factor of spinal muscular atrophy (SMA). Remarkably, risdiplam, the first orally active small-molecule RNA splicing modifier, was approved by FDA in 2020 for the treatment of SMA. Similarly, Novartis is running Phase 2 clinical trials to treat Huntington's Disease with its small-molecule RNA splicing modifier, branaplam.
Overall, RNA splicing modifier is an emerging concept extending drug discovery beyond conventional protein-based R&D. At ScinnoHub, we set forth into this vast but unexplored RNA territories with techniques in medicinal chemistry, cell and molecular biology, RNA biology, etc. in order to discover treatment with novel mechanism of action (MOA). The path is challenging, but the future is promising.
At ScinnoHub, we set forth into this vast but unexplored RNA
territories with techniques in medicinal chemistry, cell and
molecular biology, RNA biology, etc. in order to discover
treatment with novel mechanism of action (MOA)
territories with techniques in medicinal chemistry, cell and
molecular biology, RNA biology, etc. in order to discover
treatment with novel mechanism of action (MOA)
References
1. Naryshkin NA, Weetall M, et al. Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science. 2014;345(6197):688-93.
2. Lee SC, Abdel-Wahab O. Therapeutic targeting of splicing in cancer. Nat Med. 2016;22(9):976-86.
3. Ratni H, Ebeling M, et al. Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 (SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA). J Med Chem. 2018;61(15):6501-6517.
4. Cheung AK, Hurley B, et al. Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA). J Med Chem. 2018;61(24):11021-11036.
5. Darras BT, Masson R, et al. Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls. N Engl J Med. 2021;385(5):427-435.
