Author: Li, Leping ; Yang, Maozhi ; Li, Dongsheng ; Jiang, Shujuan ; Sun, Kang ; Xie, Qing ; Tu, Wangyang ; Zhang, Yixiang ; Yu, Songda ; Yu, Bing ; Liu, Lei ; Cai, Yalei

SOS1, a guanine nucleotide exchange factor (GEF), plays a critical role in catalyzing the conversion of KRAS from its GDP- to GTP-bound form, regardless of KRAS mutation status, and represents a promising new drug target to treat all KRAS-driven tumors.Herein, we employed a scaffold hopping strategy to design, synthesize, and optimize a series of novel binary ring derivatives as SOS1 inhibitors.Among them, compound 10f (HH0043) displayed potent activities in both biochem. and cellular assays and favorable pharmacokinetic profiles.Oral administration of HH0043 resulted in a significant tumor inhibitory effect in a s.c. KRAS^G12C-mutated NCI-H358 (human lung cancer cell line) xenograft mouse model, and the tumor inhibitory effect of HH0043 was superior to that of BI-3406 at the same dose (total growth inhibition, TGI: 76% vs 49%).On the basis of these results, HH0043, with a novel 1,7-naphthyridine scaffold that is distinct from currently reported SOS1 inhibitors, is nominated as the lead compound for this discovery project.

01 Jul 2023·Molecular carcinogenesis

Translational relevance of SOS1 targeting for KRAS-mutant colorectal cancer.

Article

Author: Yang, Xinrui ; Fernandez-Zapico, Martin E. ; Hogenson, Tara L. ; Beato, Francisca ; Tan, Aik Choon ; Jiang, Kun ; Cai, Jianfeng ; Yuan, Yu ; Sarcar, Bhaswati ; Dai, Ruifan ; Fleming, Jason B. ; Tassielli, Alexandra F. ; Park, Margaret A. ; Xie, Hao ; Alem, Diego

It has been challenging to target mutant KRAS (mKRAS) in colorectal cancer (CRC) and other malignancies. Recent efforts have focused on developing inhibitors blocking molecules essential for KRAS activity. In this regard, SOS1 inhibition has arisen as an attractive approach for mKRAS CRC given its essential role as a guanine nucleotide exchange factor for this GTPase. Here, we demonstrated the translational value of SOS1 blockade in mKRAS CRC. We used CRC patient-derived organoids (PDOs) as preclinical models to evaluate their sensitivity to SOS1 inhibitor BI3406. A combination of in silico analyses and wet lab techniques was utilized to define potential predictive markers for SOS1 sensitivity and potential mechanisms of resistance in CRC. RNA-seq analysis of CRC PDOs revealed two groups of CRC PDOs with differential sensitivities to SOS1 inhibitor BI3406. The resistant group was enriched in gene sets involving cholesterol homeostasis, epithelial-mesenchymal transition, and TNF-α/NFκB signaling. Expression analysis identified a significant correlation between SOS1 and SOS2 mRNA levels (Spearman's ρ 0.56, p < 0.001). SOS1/2 protein expression was universally present with heterogeneous patterns in CRC cells but only minimal to none in surrounding nonmalignant cells. Only SOS1 protein expression was associated with worse survival in patients with RAS/RAF mutant CRC (p = 0.04). We also found that SOS1/SOS2 protein expression ratio >1 by immunohistochemistry (p = 0.03) instead of KRAS mutation (p = 1) was a better predictive marker to BI3406 sensitivity of CRC PDOs, concordant with the significant positive correlation between SOS1/SOS2 protein expression ratio and SOS1 dependency. Finally, we showed that GTP-bound RAS level underwent rebound even in BI3406-sensitive PDOs with no change of KRAS downstream effector genes, thus suggesting upregulation of guanine nucleotide exchange factor as potential cellular adaptation mechanisms to SOS1 inhibition. Taken together, our results show that high SOS1/SOS2 protein expression ratio predicts sensitivity to SOS1 inhibition and support further clinical development of SOS1-targeting agents in CRC.

01 May 2023·Journal of Pharmacology and Experimental Therapeutics

Combining SOS1 and MEK Inhibitors in a Murine Model of Plexiform Neurofibroma Results in Tumor Shrinkage

Article

Author: Rizvi, Tilat A ; Trapani, Francesca ; Fugate, Elizabeth ; Maier, Udo ; Boehmelt, Guido ; Wu, Jianqiang ; Ahmari, Niousha ; Long, Clive J ; Hofmann, Marco H ; Dombi, Eva ; Düchs, Matthias J ; Ratner, Nancy ; Arnhof, Heribert ; Kim, Mi-Ok ; Jackson, Mark

Individuals with neurofibromatosis type 1 develop rat sarcoma virus (RAS)-mitogen-activated protein kinase-mitogen-activated and extracellular signal-regulated kinase (RAS-MAPK-MEK)-driven nerve tumors called neurofibromas. Although MEK inhibitors transiently reduce volumes of most plexiform neurofibromas in mouse models and in neurofibromatosis type 1 (NF1) patients, therapies that increase the efficacy of MEK inhibitors are needed. BI-3406 is a small molecule that prevents Son of Sevenless (SOS)1 interaction with Kirsten rat sarcoma viral oncoprotein (KRAS)-GDP, interfering with the RAS-MAPK cascade upstream of MEK. Single agent SOS1 inhibition had no significant effect in the DhhCre;Nf1 ^fl/fl mouse model of plexiform neurofibroma, but pharmacokinetics (PK)-driven combination of selumetinib with BI-3406 significantly improved tumor parameters. Tumor volumes and neurofibroma cell proliferation, reduced by MEK inhibition, were further reduced by the combination. Neurofibromas are rich in ionized calcium binding adaptor molecule 1 (Iba1)+ macrophages; combination treatment resulted in small and round macrophages, with altered cytokine expression indicative of altered activation. The significant effects of MEK inhibitor plus SOS1 inhibition in this preclinical study suggest potential clinical benefit of dual targeting of the RAS-MAPK pathway in neurofibromas. SIGNIFICANCE STATEMENT: Interfering with the RAS-mitogen-activated protein kinase (RAS-MAPK) cascade upstream of mitogen activated protein kinase kinase (MEK), together with MEK inhibition, augment effects of MEK inhibition on neurofibroma volume and tumor macrophages in a preclinical model system. This study emphasizes the critical role of the RAS-MAPK pathway in controlling tumor cell proliferation and the tumor microenvironment in benign neurofibromas.

100 Deals associated with BI-3406

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	FORMA Therapeutics, Inc.	19 Aug 2020
Neoplasms	Preclinical	DE	Boehringer Ingelheim GmbH	19 Aug 2020

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