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) proteins.1
BI 1701963 is currently being investigated in Phase I trials involving patients with KRAS mutation-positive solid tumours.2
Role of KRAS and SOS1
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 signalling pathway that regulates gene expression and prevents apoptosis.3
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.3
BI 1701963’s mechanism of action
BI 1701963 is a protein::protein inhibitor that binds to SOS1, thereby preventing its interaction with KRAS in the GDP-bound ‘off’ state and impeding the formation of GTP-loaded KRAS in the active ‘on’ state. Reduced levels of GTP-loaded KRAS prevent activation of downstream signalling pathways (e.g. RAF/MEK/ERK) that control proliferation and survival of cells.1 SOS1 inhibitors also antagonise the negative feedback relief induced by RAF/MEK/ERK pathway inhibitors.1
While SOS1 inhibition yields cytostasis in cancer cells addicted to KRAS signalling, the combination of a SOS1 inhibitor with a MEK inhibitor results in a more profound blockade of KRAS signalling, induction of apoptosis and tumour regression in preclinical mouse models of KRAS-driven cancers.1 Hence, there is a strong rationale for development in combination with MEK inhibitors.
BI 1701963’s mechanism of action1
ERK, extracellular signal-regulated kinases; GDP, guanosine diphosphate; GTP, guanosine triphosphate; KRAS, Kirsten rat sarcoma; MEK, mitogen-activated protein kinase; P, phosphate; SOS1, Son of sevenless homolog 1.
BI 1701963 is currently being investigated as a monotherapy and in combination with the mitogen-activated protein kinase pathway inhibitor trametinib, in patients with KRAS mutation-positive solid tumours who progressed despite appropriate prior standard therapies.2
KRAS mutation-positive solid tumours and NSCLC
AE, adverse event; DLT, dose-limiting toxicity; DoR, duration of response; KRAS, Kirsten rat sarcoma; MTD, maximum tolerated dose; OR, objective response; PFS, progression-free survival; PK, pharmacokinetics; SOS1, Son of sevenless homolog 1.
Boehringer Ingelheim. Data on file.
ClinicalTrials.gov. NCT04111458. https://clinicaltrials.gov/ct2/show/NCT04111458 (Accessed: October 2019)
Evelyn CR, et al. Chem Biol 2014;21:1618‒28.
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Last updated: October 2019
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