αvβ6; Integrins αvβ6 (KD = 5.7 nM) and αvβ1 (KD = 3.4 nM)

In precision sectioned lung sections (PCLS), bexotegrast (PLN-74809; 1.82 µM; intestinal 7 days) significantly decreased collagen type I alpha I (COL1A1) mRNA expression by 54%. There is less Smad2 phosphorylation in bexotegrast. In PCLS produced from fibrotic lungs, bexotegrast (1.82 µM; workstation 3 days) self-regulates up to a 71% reduction in Col1a1 mRNA expression [2]. αvβ6 integrin is totally blocked by bexotegrast. Approximately 50%[2]. LAP is labeled by normal human epithelial cells with an IC50 of 39.3 nM[2].

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Inhibiting TGF - β activation: Bexotegrast (PLN - 74809) can block multiple TGF - β activation pathways in fibrotic lung cells by inhibiting integrins αvβ6 and αvβ1. It can reduce the expression of type I collagen gene by inhibiting the activation of TGF - β [1]

Bexotegrast (PLN-74809; sidewall; 100, 250, 500 mg/kg; twice daily; from day 7 to day 21) was provided at levels necessary to inhibit bleomycin-challenged cartilage interstitial fibrillar collagen deposition. Bexotegrast dosage.

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Anti - fibrotic effect: In bleomycin - challenged mice, Bexotegrast (PLN - 74809) can dose - dependently inhibit pulmonary Smad3 phosphorylation and collagen deposition, reducing pulmonary fibrosis burden. It has a better antifibrotic effect than nintedanib or pirfenidone, and can more effectively reduce collagen gene expression in fibrotic mouse lung tissue [2]

Animal/Disease Models: C57BL/6 mice [2]
Doses: 100, 250, 500 mg/kg
Route of Administration: Oral; strongly bursts Smad3 phosphorylation [2]. twice (two times) daily; from day 7 to day 21
Experimental Results: There was a dose-dependent significant reduction in interstitial fibrillar collagen deposition in mice challenged with bleomycin (3 units/kg). Dose-dependent blockade of Smad3 phosphorylation.

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Bleomycin - induced lung fibrosis mouse model: Use bleomycin to induce lung fibrosis in mice. Then, administer Bexotegrast (PLN - 74809) to the mice, and set up different dose - groups. After a certain period of treatment, sacrifice the mice, collect lung tissues, and detect the changes of pulmonary collagen deposition and Smad3 phosphorylation, so as to evaluate the antifibrotic effect of the drug [2]

Pharmacokinetics [Am J Respir Crit Care Med . 2024 Aug 15;210(4):424-434.]
Predicted total and unbound exposures (maximum concentration and area under the concentration time curve from Time 0 to 24 hours postdose) of bexotegrast in participants with IPF increased approximately proportionally with dose (see Tables E3 and E4).

Safety and Tolerability through Week 12 [Am J Respir Crit Care Med . 2024 Aug 15;210(4):424-434.]
Overall, bexotegrast demonstrated a favorable safety and tolerability profile over 12 weeks of treatment (Tables 2, 3, E1, and E2 in the online supplement). The majority of TEAEs were mild or moderate in severity. The most common TEAEs are presented in Table 2. Diarrhea was the most common TEAE, occurring in 15 participants (16.9%) in the bexotegrast (pooled) group and 3 participants (9.7%) in the placebo group. Of the participants reporting diarrhea, 13/15 (86.7%) participants in the bexotegrast group and 1/3 (33.3%) participants in the placebo group were receiving nintedanib background therapy; one participant (6.7%) with diarrhea in the bexotegrast group was receiving pirfenidone (Table 3). The remaining participant with diarrhea who received bexotegrast monotherapy had preexisting ulcerative colitis. Most events of diarrhea (14/15; 93.3%) were mild to moderate in severity; one participant receiving bexotegrast and pirfenidone had Grade 3 diarrhea. Four participants interrupted bexotegrast treatment because of intercurrent coronavirus disease (COVID-19) (n = 1), diarrhea (n = 2), and ileus and acute kidney injury (n = 1). Two participants discontinued bexotegrast because of mild diarrhea (n = 1 receiving background nintedanib; n = 1 receiving no background therapy and having preexisting ulcerative colitis). Dose reduction of bexotegrast was not allowed per protocol. No serious adverse events were assessed as being related to the study drug.
TEAEs of IPF/pulmonary fibrosis were reported in 2.3% of participants in the bexotegrast group and 9.7% of participants in the placebo group. Only one of these events was reported as an acute exacerbation of IPF in a participant who had completed 12 weeks of treatment with 160 mg bexotegrast and experienced the event 11 days after the last dose. The event was not considered to be drug related and resolved the following day after treatment in hospital with corticosteroids and antibiotics. One participant with gender-age-physiology Stage III IPF and preexisting coronary artery disease and chronic refractory atrial fibrillation in the 320-mg bexotegrast group experienced a serious and fatal adverse event of acute respiratory failure after elective atrioventricular node ablation. There were no notable changes in laboratory parameters, vital signs, physical examination findings, or electrocardiography findings associated with the study drug. Overall, bexotegrast was well tolerated when used in combination with IPF background therapy or when used as monotherapy (Tables 3, E1, and E2).

[1]. De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8. Nat Commun. 2023 Sep 13;14(1):5660.

[2]. Dual inhibition of αvβ6 and αvβ1 reduces fibrogenesis in lung tissue explants from patients with IPF. Respir Res. 2021 Oct 19;22(1):265.

αv integrins are key regulators of TGF - β activation and fibrogenesis in pulmonary fibrosis models. αvβ6 and αvβ1 are highly expressed in the lung tissue of patients with idiopathic pulmonary fibrosis, while they are rarely expressed in normal tissues. Bexotegrast (PLN - 74809) is a small - molecule oral drug, which can block the activation of TGF - β by αvβ6 and αvβ1, and may slow down or even stop the fibrosis process in patients with idiopathic pulmonary fibrosis. The phase Ⅱ/Ⅲ clinical trial of treating IPF is in progress [2]
PLN-74809 is a small-molecule that dually inhibits both αvβ6 and αvβ1 to treat both idiopathic pulmonary fibrosis (IPF) and primary sclerosing cholangitis (PSC). The compound was granted orphan drug designation by the US FDA in August 2018 for treatment of IPF, and Pliant Therapeutics recently raised $100 million in Series C financing to support further clinical development of this compound. Phase 2a studies are currently evaluating PLN-74809 safety and efficacy for participants with IPF (NCT04396756)across 10 participating countries, and for participants with PSC (NCT04480840). In addition, the compound is also currently in Phase 2a trials (NCT04565249) for the treatment of COVID-19 related acute respiratory distress syndrome.

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Drug Indication
Through dual inhibition of integrins αvβ6 and αvβ1, PLN-74809 reduces subsequent activation of TGF-β1, which is actively involved in the growth of fibrotic tissue in lung and bile ducts. Further studies showed that PLN-74809 inhibited collagen gene expression in PSC and IPF patient tissue.

C27H36N6O3

492.61

492.28

C, 65.83; H, 7.37; N, 17.06; O, 9.74

2376257-44-0

2376264-69-4 (R-isomer); 2376257-44-0;2775365-40-5 (HCl);2775365-33-6 (fumarate); 2775365-31-4 (phosphate);

135390719

White to off-white solid powder

1.8

3

9

14

36

655

1

COCCN(CCCCC1=NC2=C(CCCN2)C=C1)CC[C@@H](C(=O)O)NC3=NC=NC4=CC=CC=C43

CWOFQJBATWQSHL-DEOSSOPVSA-N

InChI=1S/C27H36N6O3/c1-36-18-17-33(15-5-4-8-21-12-11-20-7-6-14-28-25(20)31-21)16-13-24(27(34)35)32-26-22-9-2-3-10-23(22)29-19-30-26/h2-3,9-12,19,24H,4-8,13-18H2,1H3,(H,28,31)(H,34,35)(H,29,30,32)/t24-/m0/s1

(S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid

PLN-74809; PLN 74809; PLN-74,809; Bexotegras; Bexotegras [INN]; (S)-4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; (S)-4-[(2-Methoxyethyl)[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]amino]-2-(quinazolin-4-ylamino)butanoic Acid; Bexotegrast; 2376257-44-0; QCV154PFT4; PLN74809; Bexotegrast; Bexotegrast free base,

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 250 mg/mL (507.50 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.22 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.22 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.22 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)