Friday, August 7, 2015

Drugs in Clinical Pipeline: LOXO-101

LOXO-101 [(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide] is a potent, ATP-competitive Tropomyosin Receptor Kinase (TRK) inhibitor with IC50s in low nanomolar range for inhibition of all TRK family members (TRKA, TRKB and TRKC) in binding and cellular assays. An enzyme-linked immunosorbant assay (ELISA) based TRKA kinase activity of LOXO-101 is reported to be 9.7 nM [1]. IC50s in range of 2 to 20 nM are reported for TRKB and TRKC (cell and enzymatic).

Trk family protein tyrosine kinase inhibition is felt to be useful in the treatment of pain, inflammation, cancer, and certain infectious diseases. LOXO-101 has demonstrated potent inhibition of TRKA in tumor bearing animals and was effective in inhibiting tumor growth in a TRKA driven malignancy. LOXO-101 is an orally bioavailable first-in-class kinase inhibitor developed specifically for TRK inhibition with favorable PK and drug metabolism properties in animals. A Phase 1 clinical study has been initiated to determine its PK, PD, safety and anti-tumor activity in humans.

The selectivity of LOXO-101 for TRK family can be assessed from following points:

1. No inhibition of greater than 200 other kinases at 1 uM
2. Weak inhibition of TNK2 (IC­50 greater than 1 uM)
3. Greater than 100-fold selective for other kinases
4. 1000-fold selective for greater than 75 non-kinase targets

The activity of LOXO-101 is as follows:

IC50 (TRKA enzyme assay) = 9.7 nM

Common Name: LOXO-101
Synonyms: LOXO-101; LOXO101; LOXO 101
IUPAC Name: (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
CAS Number: 1223403-58-4
Mechanism of Action: Kinase Inhibitor; pan-TRK Inhibitor
Indication: Various Cancers; Analgesics
Development Stage: Phase I
Company: Loxo Oncology and Array BioPharma

TRK's are the high affinity receptor tyrosine kinases activated by a group of soluble growth factors called neurotrophins (NT). The TRK receptor family has three members-TRKA, TRKB and TRKC. Among the neurotrophins are (i) nerve growth factor (NGF) which activates TRKA, (ii) brain-derived neurotrophic factor (BDNF) and NT-4/5 which activate TRKB and (iii) NT3 which activates TRKC.

1. Haas, J.; et. al. Substituted pyrazolo[1,5-a]pyrimidine compounds as trk kinase inhibitors. WO2010048314A1