SOS1::KRAS inhibitor (BI 1701963)

SOS1::KRAS inhibitor (BI 1701963)

BI 1701963: a SOS1::KRAS inhibitor

BI 1701963* is a first-in-class protein::protein interaction inhibitor that binds the Son of sevenless homolog 1 (SOS1), thereby inhibiting the interaction and activation of the key cancer driver Kirsten rat sarcoma (KRAS).1

Clinical trials: BI 1701963 is currently being investigated in Phase I trials involving patients with KRAS-mutant solid tumors, KRAS-mutant advanced colorectal cancer, and KRAS-mutant advanced solid tumors that failed previous chemotherapy.2-4

Role of KRAS and SOS1

Wild-type KRAS functions as a molecular switch that can exist in either a guanosine diphosphate-(GDP-)bound ‘off’ state, or a guanosine triphosphate-(GTP-)bound ‘on’ state. The KRAS–GTP ‘on’ state activates downstream effector pathways, including the RAF/MEK/ERK signaling pathway that regulates gene expression and prevents apoptosis.5

SOS1 is one of the guanine nucleotide exchange factors that regulates the KRAS GDP–GTP cycle and promotes nucleotide exchange and formation of ‘active’ KRAS–GTP.5

About BI 1701963

Mechanism of action

BI 1701963 is a KRAS inhibitor that works by blocking the interaction between KRAS and SOS1. By binding to SOS1, BI 1701963 effectively prevents guanine nucleotide exchange. As a result, KRAS remains in its GDP-bound ‘off’ state. Reduced levels of GTP-loaded KRAS prevent activation of downstream signaling pathways (e.g. RAF/MEK/ERK) that control proliferation and survival.1 SOS1 inhibition also reduces the negative-feedback relief that is induced by RAF/MEK/ERK pathway inhibitors.1

Although SOS1 inhibition yields cytostasis in cancer cells addicted to KRAS signaling, the combination of a SOS1 inhibitor with a MAPK kinase (MEK) inhibitor results in a more profound blockade of KRAS signaling, induction of apoptosis and tumor regression in preclinical mouse models of KRAS-driven cancers.1 Hence, there is a strong rationale for development in combination with MEK inhibitors.

SOS1::KRAS inhibitor mechanism of action1

SOS1::KRAS inhibitor mechanism of action
ERK, extracellular signal-regulated kinases; GDP, guanosine diphosphate; GTP, guanosine triphosphate; KRAS, Kirsten rat sarcoma; MEK, mitogen-activated protein kinase kinase; P, phosphate; SOS1, Son of sevenless homolog 1.

Watch the SOS1::KRAS inhibitor mechanism of action animation

Watch the SOS1::KRAS inhibitor mechanism of action animation

Clinical development

BI 1701963 is currently being investigated as a monotherapy and in combination with the MEK inhibitor trametinib in clinical trials in patients with KRAS mutation-positive solid tumors who progressed despite appropriate prior standard therapies,2 and in combination with irinotecan in patients with KRAS-mutated advanced CRC,3  and in combination with MEK inhibitor BI 3011441 in patients with KRAS mutation-positive advanced solid tumors who failed previous chemotherapy.4

Boehringer Ingelheim has also entered into a clinical trial collaboration with Mirati Therapeutics to study BI 1701963 in combination with MRTX849, a KRAS G12C selective inhibitor, in patients with solid tumors that harbor the KRAS G12C mutation.6 

More information about Boehringer Ingelheim oncology clinical trials can be found on the MyStudyWindow website. Relevant trials for our SOS1::KRAS inhibitor include: BI 1432-0001, BI 1432-0008, and BI 1432-0006.

SOS1::KRAS inhibitor (BI 1701963) clinical trials

CRC, colorectal cancer; KRAS, Kirsten rat sarcoma; MEK, mitogen-activated protein kinase kinase.
Trial number Phase Treatment Patient population Status

NCT041114582 (1432.1)

I

BI 1701963 alone and in combination with trametinib

Patients with KRAS-mutant solid tumors who progressed despite appropriate prior standard therapies

Recruiting

NCT046271423 (1432.8)

I

BI 1701963 alone and in combination with irinotecan

Patients with unresectable, locally advanced or metastatic CRC with a KRAS mutation

Recruiting

NCT048357144 (1432.6)

I

BI 1701963 inhibitor alone and in combination with MEK inhibitor BI 3011441

Patients with KRAS-mutant advanced solid tumors who failed previous chemotherapy

Recruiting

Explore our latest SOS1::KRAS inhibitor data

Our latest data on the SOS1::KRAS inhibitor (BI 1701963) were presented at the American Association for Cancer Research Congress 2021.

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References

1

Boehringer Ingelheim. Data on file.

2

ClinicalTrials.gov. NCT04111458. https://clinicaltrials.gov/ct2/show/NCT04111458 (Accessed: July 2021)

3

ClinicalTrials.gov. NCT04627142. https://clinicaltrials.gov/ct2/show/NCT04627142 (Accessed: July 2021).

4

ClinicalTrials.gov. NCT04835714. https://clinicaltrials.gov/ct2/show/NCT04835714 (Accessed: July 2021).

5

Evelyn CR, et al. Chem Biol 2014;21:1618‒28.

6

Boehringer Ingelheim. Press release. https://www.boehringer-ingelheim.com/press-release/clinicalcollaborationwithmirati (Accessed: February 2021).

*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.

 

© 2021 Boehringer Ingelheim International GmbH. All rights reserved.

 

Last updated: May 2021