SOS1 inhibitors are compounds designed to interact with the Son of Sevenless homolog 1 (SOS1) protein. Scientists are investigating how these inhibitors can modulate biological processes, offering a new avenue for understanding and potentially addressing various health conditions. This research reflects a broader effort to develop targeted therapeutic approaches.
The Role of SOS1 in Cellular Processes
Son of Sevenless homolog 1 (SOS1) is a protein that regulates cell functions, including growth, division, differentiation, movement, and programmed cell death. It acts as a guanine nucleotide exchange factor (GEF) for RAS proteins, which are molecular switches. SOS1 facilitates this exchange, promoting RAS protein activation.
SOS1 activation of RAS proteins initiates the RAS/MAPK signaling pathway. This pathway regulates many cellular processes, ensuring proper cell development and tissue control. Overactive or dysregulated SOS1 can lead to constant RAS activation, disrupting normal cell growth and division.
Such dysregulation contributes to conditions like Noonan syndrome and hereditary gingival fibromatosis type 1. In Noonan syndrome, SOS1 gene mutations cause continuous protein activation and uncontrolled cell growth. A specific SOS1 gene mutation also causes hereditary gingival fibromatosis type 1, characterized by excessive gum tissue growth.
Mechanism of SOS1 Inhibitors
SOS1 inhibitors interfere with the SOS1 protein’s ability to activate RAS. These compounds bind specifically to SOS1, altering its shape. This binding prevents SOS1 from properly interacting with RAS proteins.
The primary action of SOS1 inhibitors is to block the conversion of inactive RAS to its active form. By disrupting this exchange, inhibitors reduce hyperactive RAS signaling that drives uncontrolled cell growth. This aims to restore normal cellular signaling.
Instead of directly targeting RAS, which has been challenging for drug development, SOS1 inhibitors target an upstream activator. This indirect approach modulates the RAS pathway. For example, BAY-293 inhibits the interaction between KRAS and SOS1, preventing KRAS from being reloaded with GTP and inhibiting cell proliferation.
Targeting Cancer with SOS1 Inhibitors
SOS1 inhibitors show promise in cancer treatment, especially for cancers driven by RAS gene mutations. RAS mutations are prevalent, found in about 30% of human cancers, including pancreatic, lung, and colorectal cancers. These mutations lock RAS proteins in an active state, continuously driving cell growth.
Directly targeting mutated RAS proteins has been difficult, leading them to be considered “undruggable.” SOS1 inhibitors offer an indirect strategy by inhibiting upstream RAS activation. By blocking SOS1, these inhibitors aim to reduce active RAS levels, even when RAS is mutated.
Preclinical studies show SOS1 inhibitors can reduce tumor growth in models of lung, colorectal, and pancreatic cancers. SOS1 inhibition can decrease phospho-ERK activity, a downstream indicator of RAS pathway activation, even in cancer cell lines with mutated KRAS. This approach is being explored for its potential to address RAS-driven malignancies.
Current Progress in SOS1 Inhibitor Research
Research into SOS1 inhibitors has advanced, with several compounds in various development stages. As of September 2023, 22 SOS1 drugs from 27 organizations were reported worldwide, covering 14 indications and undergoing 9 clinical trials. Many are small molecule drugs.
Some SOS1 inhibitors, like BI-1701963 and MRTX0902, have entered early-phase clinical trials (Phase 1/2). BI-1701963 is being investigated in patients with KRAS mutation-positive solid tumors. BAY3498264, an oral selective SOS1 inhibitor, entered a Phase I clinical trial in November 2024, evaluating its safety and efficacy, especially with sotorasib for advanced KRAS G12C-mutated solid tumors.
Researchers face challenges in developing SOS1 inhibitors, including ensuring high specificity and managing potential resistance mechanisms. However, combining SOS1 inhibitors with other targeted therapies, such as KRAS G12C inhibitors, shows potential for enhanced anti-tumor responses and overcoming resistance.