29 November 2021 - - US-based oncology company Scorpion Therapeutics, Inc has revealed its two lead programs, both targeting well-known, clinically validated, mutated oncogenes, the company said.

The first program, STX-H1047-PI3Kα, targets the H1047X-mutant form of phosphoinositide 3-kinase alpha, a cancer driver associated with a wide variety of solid tumors.

The second program, STX-EGFR-EXON20, selectively targets exon 20 insertion mutations in epidermal growth factor receptor, which drives non-small cell lung cancer.

The rapid discovery of both STX-H1047-PI3Kα and STX-EGFR-EXON20 was enabled by Scorpion's fully integrated, fit-for-purpose drug-hunting platform, which integrates more than 20 years of cutting-edge advances across cancer biology, medicinal chemistry, and data sciences with the aim to redefine the frontier of precision medicine.

Scorpion leverages its platform to address a wider array of targets with higher quality medicines than previously possible and to fill therapeutic white spaces of underserved patient populations.

Scorpion is focused on three categories: best-in-class molecules targeting validated oncogene targets; first-in-class molecules for previously undruggable targets, including a number of transcription factors and validated synthetic lethal targets; and first-in-class molecules for novel cancer target classes.

The PI3Kα and EGFR programs fall into the first category.

STX-H1047-PI3Kα: PI3Kα is an established cancer target and one of the most highly mutated targets in cancer, particularly in solid tumors.

The mutations at the H1047 residue represent the highest frequency of mutations in PI3Kα.

More than 55,000 people in the United States annually are diagnosed with cancers driven by mutations at this residue.

Approved therapies targeting PI3Kα are limited by inhibition of the normal, or wild-type, version of PI3Kα in healthy tissues, leading to significant metabolic side effects that hinder the ability of patients to tolerate these therapies, and by an inability to treat tumors that have progressed into the central nervous system.

Using its drug-hunting platform, Scorpion discovered a novel allosteric binding pocket that allows for specific targeting of the mutant over the wild-type form of PI3Kα with a small molecule.

This may allow for maximal inhibition of the mutant protein in cancer cells compared to normal tissues, to avoid the off-target effects such as metabolic dysfunction that are associated with wild-type inhibition by commercially available options.

STX-H1047-PI3Kα is designed to be a central nervous system-penetrant, oral pill. In preclinical studies, STX-H1047-PI3Kα has demonstrated exquisite in vitro selectivity and dose-dependent anti-tumor activity, without evidence of hyperglycemia in multiple model systems.

Scorpion expects to submit an IND for STX-H1047-PIK3α in 2023.

STX-EGFR-EXON20: NSCLC is the most common form of lung cancer and EGFR mutations are one of the most common mutations in NSCLC.

NSCLC tumors that express EGFR with Exon 20 insertion mutations have an incidence of approximately 3,400 patients per year in the United States.

Commercially-available therapies for NSCLC patients with EGFR Exon 20 insertion mutations are limited by significant toxicities associated with the inhibition of wild-type EGFR protein in healthy tissues such as the skin and gut, leaving a significant unmet need for those patients.

Leveraging its discovery platform, Scorpion identified highly differentiated chemical matter that provides exquisitely selective inhibition of Exon 20 insertion mutations compared to the wild-type form of the protein.

This may allow for maximal inhibition of the mutant protein in cancer cells compared to normal tissues, thereby reducing the toxicities often gastrointestinal or skin-related that lead to dose limitations or reductions with existing EGFR exon 20 inhibitors.

STX-EGFR-EXON20 is designed as an oral pill, which in preclinical studies demonstrated best-in-class selectivity and dose-dependent anti-tumor activity in xenograft models at well-tolerated doses. Scorpion expects to submit an IND for STX-EGFR-EXON20 in 2023.

Scorpion Therapeutics is an oncology company redefining the frontier of precision medicine to deliver optimized and transformational therapies for larger populations of patients with cancer, a strategy Scorpion refers to as Precision Oncology 2.0.