STC-15, a novel METTL3 inhibitor

1. Background

STORM’s lead clinical program STC-15 is a first-in-class inhibitor of RNA modification and is the first ever RNA methyltransferase inhibitor to enter clinical development. STC-15 is an oral small molecule that inhibits METTL3, an RNA methyltransferase implicated in oncology and other diseases. Certain RNA methyltransferases are important regulators of RNA sensing and innate immune activation and represent novel immune-regulatory targets.

STC-15 has also been shown to inhibit tumor growth through mechanisms involving anti-cancer immune responses such as changes in interferon signaling and synergy with T cell checkpoint blockade. In addition, this compound, has demonstrated efficacy in leukemia models via mechanisms such as inhibition of leukemia stem cell function.

Now oral Administration of STC-15 in Subjects With Advanced Malignancies (NCT05584111) is recruiting—details description as below.

This Phase 1, multi-center, open-label, first-in-human study evaluates multiple ascending daily oral doses of STC-15 in Q3W treatment cycles in a 3+3 cohort design with dose levels determined by a modified Fibonacci algorithm. The study is designed to systematically assess safety and tolerability, pharmacokinetics, pharmacodynamics and clinical activity of STC-15 in adult subjects with advanced malignancies. Dose levels for further evaluation in expansion cohorts will be selected based on all available PK, pharmacodynamic, target engagement, efficacy, safety, and tolerability data including long-term safety data beyond dose limiting toxicities (DLTs). The study may be amended to evaluate STC-15 in combination with a Food and Drug Administration-approved standard of care treatment regimen, which could encompass targeted/chemotherapy, radiation therapy and/or immunotherapy with immune checkpoint blockers.

2. Chemistry Structure and synthesis route of STC-15.

a) Intermediates of STC-15

b) patents and related literature.

WO2021111124A1
WO2022254218A1
Abstract A18_ STC-15, a novel METTL3 inhibitor, and its combination with Venetoclax confer anti-tumour activity in AML models _ Blood Cancer Discovery _ American Association for Cancer Research

3. Activity of STC-15

a) Model of action

RNA methyltransferase – methylates N6- position of A (m6A) in selected mRNAs, m6A regulates mRNA translation and stability, inhibition of METTL3 and loss of m6A can inhibit key oncogenes, Inhibition of METTL3 activates innate immune responses in cancer cells via induction of dsRNA.

1）METTL3 is an RNA methyltransferase responsible for the deposition of N-6- methyladenosine (m6A) modification on mRNA and long non-coding RNA (lncRNA) targets, to regulate their stability, splicing, transport and translation. Orally bioavailable small molecule METTL3 inhibitor STC-15 inhibits cancer growth and induces anti- cancer immunity, by mechanisms involve the activation of CD8+ cytotoxic T- cells

2）METTL3 has been implicated in the initiation and progression of multiple cancer types, with the highest expression of METTL3 mRNA observed in acute myeloid leukemia (AML). Currently, one line of standard of care therapy for AML patients is Venetoclax, which targets the anti-apoptotic protein BCL2. It was shown that m6A, deposited by METTL3 on BCL2 transcript, affects BCL2 mRNA stability and translation.

3) Combination of STC-15 and Anti-PD1 Induces Tumor Regression 16 and Anti-cancer Immunity in Mouse Syngeneic Models, STC-15 / anti-PD1 Treated Mice Appear To Be Cured: No Regrowth of Regressed Tumors.

Mice with regressions are immune to the cancer (rechallenge with tumor cells fails to generate new tumors); STC-15 efficacy is CD8 T cell dependent (no activity if deplete CD8 T cells); Combination activity seen in multiple syngeneic models.