PMID- 35122773
OWN - NLM
STAT- MEDLINE
DCOM- 20220310
LR  - 20220310
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Linking)
VI  - 438
DP  - 2022 Mar 1
TI  - Lung-restricted ALK5 inhibition avoids systemic toxicities associated with TGFbeta 
      pathway inhibition.
PG  - 115905
LID - S0041-008X(22)00050-3 [pii]
LID - 10.1016/j.taap.2022.115905 [doi]
AB  - Systemic therapies targeting transforming growth factor beta (TGFbeta) or TGFbetaR1 
      kinase (ALK5) have been plagued by toxicities including cardiac valvulopathy and 
      bone physeal dysplasia in animals, posing a significant challenge for clinical 
      development in pulmonary indications. The current work aims to demonstrate that 
      systemic ALK5-associated toxicities can be mitigated through localized lung 
      delivery. Lung-selective (THRX-144644) and systemically bioavailable 
      (galunisertib) ALK5 inhibitors were compared to determine whether lung 
      selectivity is sufficient to maintain local tissue concentrations while 
      mitigating systemic exposure and consequent pathway-related findings. Both 
      molecules demonstrated potent ALK5 activity in rat precision cut lung slices 
      (PCLS; p-SMAD3 half-maximal inhibitory concentration [IC50], 141 nM and 1070 nM 
      for THRX-144644 and galunisertib, respectively). In 14-day repeat-dose studies in 
      rats, dose-related cardiac valvulopathy was recapitulated with oral galunisertib 
      at doses >/=150 mg/kg/day. In contrast, inhaled nebulized THRX-144644 did not cause 
      similar systemic findings up to the maximally tolerated doses in rats or dogs (10 
      and 1.5 mg/kg/day, respectively). THRX-144644 lung-to-plasma ratios ranged from 
      100- to 1200-fold in rats and dogs across dose levels. THRX-144644 lung trough 
      (24 h) concentrations in rats and dogs ranged from 3- to 17-fold above the PCLS 
      IC50 across tolerated doses. At a dose level exceeding tolerability 
      (60 mg/kg/day; 76-fold above PCLS IC50) minimal heart and bone changes were 
      observed when systemic drug concentrations reached pharmacologic levels. In 
      conclusion, the current preclinical work demonstrates that localized pulmonary 
      delivery of an ALK5 inhibitor leads to favorable TGFbeta pathway pharmacodynamic 
      inhibition in lung while minimizing key systemic toxicities.
CI  - Copyright (c) 2022 Theravance Biopharma Ireland Limited. Published by Elsevier Inc. 
      All rights reserved.
FAU - Maher, Jonathan M
AU  - Maher JM
AD  - Theravance Biopharma US, Inc., South San Francisco, CA, USA. Electronic address: 
      JMaher@theravance.com.
FAU - Zhang, Rui
AU  - Zhang R
AD  - Theravance Biopharma US, Inc., South San Francisco, CA, USA.
FAU - Palanisamy, Gopinath
AU  - Palanisamy G
AD  - Olema Oncology, San Francisco, CA, USA.
FAU - Perkins, Kimberly
AU  - Perkins K
AD  - Theravance Biopharma US, Inc., South San Francisco, CA, USA.
FAU - Liu, Lynda
AU  - Liu L
AD  - Theravance Biopharma US, Inc., South San Francisco, CA, USA.
FAU - Brassil, Patrick
AU  - Brassil P
AD  - Theravance Biopharma US, Inc., South San Francisco, CA, USA.
FAU - McNamara, Alexander
AU  - McNamara A
AD  - Theravance Biopharma US, Inc., South San Francisco, CA, USA.
FAU - Lo, Arthur
AU  - Lo A
AD  - Theravance Biopharma US, Inc., South San Francisco, CA, USA.
FAU - Hughes, Adam D
AU  - Hughes AD
AD  - Theravance Biopharma US, Inc., South San Francisco, CA, USA.
FAU - Kanodia, Jitendra
AU  - Kanodia J
AD  - Theravance Biopharma US, Inc., South San Francisco, CA, USA.
FAU - Kulyk, Svitlana
AU  - Kulyk S
AD  - Mirati Therapeutics, San Diego, CA, USA.
FAU - Nikula, Kristen J
AU  - Nikula KJ
AD  - Inotiv, Maryland Heights, MO, USA.
FAU - Dengler, Hart S
AU  - Dengler HS
AD  - Interline Therapeutics, South San Francisco, CA, USA.
FAU - Scandurra, Amy
AU  - Scandurra A
AD  - Theravance Biopharma US, Inc., South San Francisco, CA, USA.
FAU - Lua, Ingrid
AU  - Lua I
AD  - Theravance Biopharma US, Inc., South San Francisco, CA, USA.
FAU - Harstad, Eric
AU  - Harstad E
AD  - Theravance Biopharma US, Inc., South San Francisco, CA, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220203
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Pyrazoles)
RN  - 0 (Quinolines)
RN  - 700874-72-2 (LY-2157299)
RN  - EC 2.7.11.30 (Receptor, Transforming Growth Factor-beta Type I)
RN  - EC 2.7.11.30 (Tgfbr1 protein, rat)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Dogs
MH  - Female
MH  - Lung/drug effects/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Pyrazoles/toxicity
MH  - Quinolines/toxicity
MH  - Rats
MH  - Rats, Inbred F344
MH  - Rats, Sprague-Dawley
MH  - Receptor, Transforming Growth Factor-beta Type I/*antagonists & 
      inhibitors/metabolism
MH  - Signal Transduction/*drug effects
OTO - NOTNLM
OT  - Aerosols
OT  - Cytokines
OT  - Inhalation toxicity
OT  - Lung
OT  - Pharmaceuticals
EDAT- 2022/02/06 06:00
MHDA- 2022/03/11 06:00
CRDT- 2022/02/05 20:12
PHST- 2021/11/09 00:00 [received]
PHST- 2022/01/22 00:00 [revised]
PHST- 2022/01/25 00:00 [accepted]
PHST- 2022/02/06 06:00 [pubmed]
PHST- 2022/03/11 06:00 [medline]
PHST- 2022/02/05 20:12 [entrez]
AID - S0041-008X(22)00050-3 [pii]
AID - 10.1016/j.taap.2022.115905 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2022 Mar 1;438:115905. doi: 10.1016/j.taap.2022.115905. 
      Epub 2022 Feb 3.