Selpercatinib
[CAS# 2152628-33-4]

Identification

• Classification: API >> Antineoplastic agents
• Name: Selpercatinib
• Synonyms: 6-(2-Hydroxy-2-methylpropoxy)-4-[6-[6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile
• Molecular Formula: C₂₉H₃₁N₇O₃
• Molecular Weight: 525.60
• CAS Registry Number: 2152628-33-4
• EC Number: 843-660-2
• SMILES: CC(C)(COC1=CN2C(=C(C=N2)C#N)C(=C1)C3=CN=C(C=C3)N4CC5CC(C4)N5CC6=CN=C(C=C6)OC)O

Properties

• Solubility: Practically insoluble (0.015 g/L) (25 °C), Calc.^*
• Density: 1.36±0.1 g/cm³ (20 °C 760 Torr), Calc.^*
• Index of Refraction: 1.694, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (©1994-2019 ACD/Labs)

Safety Data

• Hazard Symbols: GHS08;GHS098 Danger
• Risk Statements: H341-H360-H60FD-H371-H373-H400-H410
• Safety Statements: P203-P260-P264-P270-P273-P280-P308+P316-P318-P319-P391-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Reproductive toxicity	Repr.	1B	H360
Germ cell mutagenicity	Muta.	2	H341
Acute hazardous to the aquatic environment	Aquatic Acute	1	H400
Specific target organ toxicity - single exposure	STOT SE	2	H371
Chronic hazardous to the aquatic environment	Aquatic Chronic	1	H410

Discovery and Applications

Selpercatinib, also known by its development name LOXO-292, was discovered through the concerted efforts of scientists at Loxo Oncology, a subsidiary of Eli Lilly and Company. Initially identified in the search for selective inhibitors of the RET (rearranged during transfection) proto-oncogene, selpercatinib was synthesized and optimized using structure-based drug design and medicinal chemistry approaches. RET fusions and mutations are implicated in various cancers, including medullary thyroid cancer and non-small cell lung cancer (NSCLC). The discovery process involved iterative cycles of molecular modification and biological testing, culminating in a compound with high specificity and potency against RET-driven cancers. Its favorable safety profile and efficacy in preclinical models led to clinical trials, resulting in its FDA approval in 2020.

Selpercatinib is highly effective in treating NSCLC patients with RET fusion-positive tumors. RET fusions occur in a small subset of NSCLC cases and are associated with poor prognosis. Selpercatinib specifically targets these genetic alterations, leading to tumor shrinkage and prolonged survival. Clinical trials have demonstrated high response rates, making it a valuable option for patients who previously had limited treatment choices. For patients with medullary thyroid cancer harboring RET mutations, selpercatinib provides a targeted therapeutic approach. Traditional treatments for MTC are limited, especially for advanced or metastatic cases. Selpercatinib inhibits RET kinase activity, which drives cancer cell proliferation and survival in these patients, leading to significant clinical benefits and manageable side effects. Beyond NSCLC and MTC, selpercatinib shows promise in treating other cancers with RET alterations, such as certain types of papillary thyroid cancer and colorectal cancer. Its ability to selectively inhibit RET signaling pathways offers potential efficacy in a broader range of RET-driven malignancies, expanding its therapeutic reach.

The LIBRETTO-001 trial was pivotal in demonstrating the safety and efficacy of selpercatinib across multiple RET-altered cancers. This global, multi-cohort study enrolled patients with advanced solid tumors harboring RET alterations, showing robust anti-tumor activity and durable responses. The trial's success led to accelerated regulatory approvals and established selpercatinib as a standard treatment option for RET-driven cancers.Selpercatinib is being explored in combination with other cancer therapies to enhance treatment efficacy and overcome resistance. Combining selpercatinib with immune checkpoint inhibitors or other targeted therapies may provide synergistic effects, offering improved outcomes for patients with complex cancer profiles or resistance to monotherapy. Selpercatinib acts by selectively inhibiting RET kinase activity, which is crucial for the growth and survival of RET-altered cancer cells. By blocking the phosphorylation of RET and its downstream signaling pathways, selpercatinib effectively halts tumor cell proliferation and induces apoptosis. Its high selectivity for RET reduces off-target effects, minimizing toxicity and improving patient tolerability. One of the challenges in targeted cancer therapy is the development of resistance. Selpercatinib addresses this by targeting multiple RET alterations, including those that confer resistance to other therapies. Its ability to bind and inhibit RET with high affinity ensures sustained efficacy, even in the presence of resistance mutations.

Research is ongoing to explore selpercatinib's potential in additional cancer types and earlier stages of disease. Investigating its role in combination with other therapies and its effectiveness in adjuvant settings could broaden its applications and improve patient outcomes across a wider spectrum of cancers. Selpercatinib represents a significant advancement in the era of personalized medicine. Its development underscores the importance of molecular profiling in identifying patients who can benefit from targeted therapies. As genomic testing becomes more integrated into clinical practice, the identification and treatment of RET-altered cancers with selpercatinib are expected to increase, leading to more personalized and effective cancer care.

References

2020. Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. The New England Journal of Medicine, 383(9).
DOI: 10.1056/nejmoa2005651

2024. Molecular genetics, therapeutics and RET inhibitor resistance for medullary thyroid carcinoma and future perspectives. Cell Communication and Signaling, 22(1).
DOI: 10.1186/s12964-024-01837-x

2024. Discovery of 7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridine derivatives as potent inhibitors of rearranged during transfection (RET) and RET solvent-front mutants for overcoming selpercatinib resistance. European Journal of Medicinal Chemistry, 279.
DOI: 10.1016/j.ejmech.2024.116891