PTC299 suppresses the synthesis of VEGFA protein in HeLa cells induced by hypoxia, with an EC50 of 1.64 ± 0.83 nM[1]. In leukemia cells, PTC299 is more than ten to thousand times more effective than Brequinar, Vidofludimus, or A 77-1726, with an IC50 of about 1 nM [1].

[1]. Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of DihydroorotateDehydrogenase with Favorable Pharmaceutical Properties. Mol Cancer Ther. 2019 Jan;18(1):3-16.

[2]. Brief Report: A Phase 1b/Pharmacokinetic Trial of PTC299, a Novel PostTranscriptional VEGF Inhibitor, for AIDS-Related Kaposi's Sarcoma: AIDS Malignancy Consortium Trial 059. J Acquir Immune Defic Syndr. 2016 May 1;72(1):52-7.

[3]. Phase I and pharmacokinetic trial of PTC299 in pediatric patients with refractory or recurrent central nervous system tumors: a PBTC study. J Neurooncol. 2015;121(1):217-224.

[4]. Zeng Z, et al, Targeting dihydroorotate dehydrogenase in acute myeloid leukemia. Haematologica. 2018 Sep;103(9):1415-1417.

PTC299 is a novel, orally administered small-molecule designed to inhibit the production of vascular endothelial growth factor (VEGF) in tumors. Overexpression of VEGF plays a key role in multiple diseases including cancer and macular degeneration. PTC299 was discovered through PTC's GEMS technology by targeting the post-transcriptional processes that regulate VEGF formation, and is currently being developed for the treatment of cancer.
Emvododstat is an orally bioavailable, small molecule inhibitor of vascular endothelial growth factor (VEGF) synthesis with potential antiangiogenesis and antineoplastic activities. Emvododstat targets post-transcriptionally by selectively binding the 5'- and 3'-untranslated regions (UTR) of VEGF messenger RNA (mRNA), thereby preventing translation of VEGF. This inhibits VEGF protein production and decreases its levels in the tumor and bloodstream. In turn, this may result in the inhibition of migration, proliferation and survival of endothelial cells, microvessel formation, the inhibition of tumor cell proliferation, and eventually the induction of tumor cell death. VEGFs are upregulated in a variety of tumor cell types and play key roles during angiogenesis. In addition, emvododstat may enhance the antitumor activity of other chemotherapeutic agents.

---

Drug Indication
Investigated for use/treatment in cancer/tumors (unspecified) and solid tumors.

---

Mechanism of Action
PTC299 was designed to inhibit VEGF production in tumors by targeting the post-transcriptional control processes that regulate VEGF formation. Because PTC299 inhibits VEGF production, its action occurs at a different point in the VEGF pathway than therapies, such as Avastin® or Sutent®. PTC299 may be active both as a single agent or when used in combination with other anti-angiogenic agents or with chemotherapy agents for the treatment of cancers.

---

Pharmacodynamics
PTC299 demonstrated a broad range of activity in blocking VEGF synthesis in multiple tumor types, including breast, cervical, colorectal, fibrosarcoma, gastric, lung, melanoma, neuroblastoma, ovarian, pancreatic, prostate and renal cell cancer lines. PTC299 as a monotherapy significantly reduced VEGF concentrations in tumors and plasma, reduced tumor blood vessel density, and substantially impeded tumor progression.

C25H20CL2N2O3

467.343904495239

466.09

C, 64.25; H, 4.31; Cl, 15.17; N, 5.99; O, 10.27

1256565-36-2

49787172

White to light yellow solid powder

6.3

1

3

4

32

651

1

COC1=CC=C(C=C1)[C@H]2C3=C(CCN2C(=O)OC4=CC=C(C=C4)Cl)C5=C(N3)C=CC(=C5)Cl

SRSHBZRURUNOSM-DEOSSOPVSA-N

InChI=1S/C25H20Cl2N2O3/c1-31-18-7-2-15(3-8-18)24-23-20(21-14-17(27)6-11-22(21)28-23)12-13-29(24)25(30)32-19-9-4-16(26)5-10-19/h2-11,14,24,28H,12-13H2,1H3/t24-/m0/s1

(4-chlorophenyl) (1S)-6-chloro-1-(4-methoxyphenyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carboxylate

PTC299; PTC 299; PTC-299

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO : ~50 mg/mL (~106.99 mM)

Solubility in Formulation 1: ≥ 0.83 mg/mL (1.78 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 8.3 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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.

---

Solubility in Formulation 2: ≥ 0.83 mg/mL (1.78 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 8.3 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

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