Boehringer Ingelheim Enters $700M R&D Collaboration to Expand KRAS Inhibitor Portfolio

Today, Boehringer Ingelheim announced a research and development agreement with Lupin Pharmaceuticals. The agreement aims to develop a combination therapy comprising Boehringer Ingelheim’s investigational KRAS inhibitor and Lupin’s novel MEK inhibitor (LNP3794), focusing on the treatment of gastrointestinal cancers, lung cancer, and other malignancies harboring oncogenic KRAS mutations.

Under the terms of the agreement, Lupin will receive a $20 million upfront payment and future milestone payments that could exceed $700 million.

RAS family proteins are widely expressed in various eukaryotes. They exist in two states within the cell: an inactive state bound to GDP and an active state bound to GTP. By switching between these two states, RAS proteins regulate multiple downstream pathways, including the MAPK signaling pathway (RAS-RAF-MEK-ERK). The MAPK pathway controls several key cellular activities, such as proliferation, differentiation, survival, and angiogenesis, with MEK serving as a critical protein kinase in this pathway.

The RAS family of proteins is primarily categorized into three major classes: KRAS, HRAS, and NRAS, with KRAS being one of the most common oncogenes. KRAS mutations occur in over 90% of pancreatic cancers, 40% of colorectal cancers, and 30% of lung adenocarcinomas, with a prevalence ratio of 1:7 in metastatic cancers. Preclinical studies have demonstrated that combining RAS inhibitors with MEK inhibitors can more effectively retard tumor growth compared to monotherapy.

Due to the smooth surface structure of RAS proteins, their hydrophobic pockets for small-molecule binding are not prominent; consequently, the RAS family has been considered "undruggable" for over three decades. Recent research findings indicate that BI-2852, an investigational KRAS inhibitor from Boehringer Ingelheim, binds to the switch I/II pocket of RAS proteins with nanomolar affinity and inhibits the GDP-GTP cycling pathway of KRAS. This mechanism differs from that of covalent KRAS G12C inhibitors.

▲Molecular structure of BI-2852 (Image source: Reference [2])

“This collaboration utilizes Boehringer Ingelheim’s KRAS inhibitor and Lupin’s novel MEK inhibitor to form an innovative combination therapy for the treatment of cancers driven by activating KRAS mutations, with the aim of providing more effective and durable responses for these patients,” said Dr. Norbert Kraut, Global Head of Cancer Research at Boehringer Ingelheim. “We believe this partnership will significantly strengthen our KRAS program. We have developed a comprehensive therapeutic approach that will successfully inhibit the oncogenic KRAS-RAF-MEK-ERK signaling pathway at its source.”

References:

[1]. Boehringer Ingelheim Expands KRAS Cancer Program with Lupin’s Clinical Stage MEK Inhibitor Compound. Retrieved Sep. 4, 2019, https://www.boehringer-ingelheim.com/press-release/expansion-kras-cancer-program-mek-inhibitor-tissue/

[2]. Fesik. et al. （2019）Drugging an undruggable pocket on KRAS. PNAS. https://doi.org/10.1073/pnas.1904529116

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