Paclitaxel is a first-line taxane-based chemotherapeutic agent for various
malignancies such as breast, ovarian, and non-small cell lung cancers. Unf
ortunately, approximately 60-70% patients develop chemotherapy-induce
d peripheral neuropathy (CIPN) after receiving it, not only diminishing life
quality but even making patients quit therapy. Thus, development of a ne
uroprotective agent to prevent or alleviate paclitaxel-induced CIPN is an u
rgent unmet medical need. Combining a unique image-based high-conte
nt screening platform with a novel phenotypic nerve assay system newly d
eveloped by our drug-discovery team, medicinal chemists have well estab
lished structure-activity relationships (SAR), leading to the identification o
f a neuroprotective drug candidate DBPR168, which has completed the proof-of-concept in two behavioral mouse models, including tail immersion
and von Frey filaments. In brief, pretreatment with DBPR168 administered
intravenously before receiving paclitaxel was able to alleviate both paclita
xel-induced thermal hypesthesia and mechanical allodynia effectively. Me
chanistically, DBPR168 could significantly inhibit paclitaxel-induced inflam
matory responses and the infiltration of immune cells into sensory neuron
s. DBPR168 not only showed a high safety dose (MTD = 500 mg/kg, IV), b
ut also a low minimum efficacy dose (MED = 10 mg/kg, IV) in mice. Based
on a high therapeutic index (50) and excellent pharmacological profiles, it
is anticipated that DBPR168 might have great potential to become the firs
t-in-class neuroprotective agent to prevent chemotherapy-induced periph
eral neuropathy (CIPN).