CUDC-907 (Synonyms: CUDC-907)

CUDC is an orally bioavailable small molecule PI3K and HDAC dual inhibitor that acts on PI3K α And HDAC1 / 2 / 3 / 10 with IC50 of 19 nm and 1.7 nm / 5 nm / 1.8 nm / 2.8 nm ^[1].

The antitumor activity of the dual function HDAC and PI3K inhibitor CUDC-907 in WSU DLCL2 cells were evaluated. It was observed that CUDC-907 inhibits cell growth and induces apoptosis with nanomolar potency. The cell cycle arrest at G2/M phase, while the expression of cyclin dependent kinase inhibitor 1 was enhanced and the expression of cyclin B was decreased when the cells treated with CUDC-907. CUDC-907 can not only inhibit the phosphorylation of Akt and mTOR and promote the acetylation of histone H3, but also significantly inhibit the phosphorylation levels of Smad2 / 3 and ERK. CUDC-907 may be a candidate drug for the treatment of systemic keloid ^[2]. CUDC-907 treatment downregulated MYC paralogs and FoxM1, induced G1 cell cycle arrest, and impaired the DNA double strand break (DSB) repair ability of SCLC cells, resulting in an effective antiproliferative effect. In addition, It was found that CUDC-907 treatment enhanced the therapeutic effect of the PARP inhibitor olaparib in SCLC cell models and PDX models. Mechanistic studies showed that cudc-907 synergized with olaparib by blocking the DSB repair pathway and downregulating myc paralogs and FoxM1 ^[3].

Human pancreatic xenograft model was established by subcutaneous injection of human pancreatic cancer Aspc-1 cells into nude mice. After 19 days of gavage, the tumor growth of Aspc-1 xenograft mice treated with 300 mg / kg cudc-907 once a day was significantly reduced compared with the vehicle group, with a T / C (%) of 43.9% (P ? < 0.01). Importantly, there was no weight loss ^[4]. It was evaluated that the in vivo role of clinical grade cudc-907 in a mouse model of fibrosis that recapitulates the clinical behavior of idiopathic pulmonary fibrosis. After intratracheal injection of bleomycin, mice were treated with 35% captisol (control) or 1 mg / kg CUDC-907 dissolved in 35% captisol. We found that cudc-907 treatment inhibited collagen accumulation. On day 18, these mice exhibited a significant attenuation of bleomycin induced total lung collagen deposition. In addition, immunohistochemical staining of left lung sections showed that cudc-907 treatment inhibited bleomycin induced total col1, col3 and α- SMA ^[5].

References:
[1] Whitfield J R, Beaulieu M E, Soucek L. Strategies to inhibit Myc and their clinical applicability[J]. Frontiers in cell and developmental biology, 2017, 5: 10.
[2] Tu T, Huang J, Lin M, et al. CUDC_x001E_907 reverses pathological phenotype of keloid fibroblasts in vitro and in vivo via dual inhibition of PI3K/Akt/mTOR signaling and HDAC2[J]. International journal of molecular medicine, 2019, 44(5): 1789-1800.
[3] Ma L, Bian X, Lin W. The dual HDAC-PI3K inhibitor CUDC-907 displays single-agent activity and synergizes with PARP inhibitor olaparib in small cell lung cancer[J]. Journal of Experimental & Clinical Cancer Research, 2020, 39(1): 1-14.
[4] Fu X, Zhang X, Yang H, et al. CUDC-907 displays potent antitumor activity against human pancreatic adenocarcinoma in vitro and in vivo through inhibition of HDAC6 to downregulate c-Myc expression[J]. Acta Pharmacologica Sinica, 2019, 40(5): 677-688.
[5] Zhang W, Zhang Y, Tu T, et al. Dual inhibition of HDAC and tyrosine kinase signaling pathways with CUDC-907 attenuates TGFβ1 induced lung and tumor fibrosis[J]. Cell death & disease, 2020, 11(9): 1-13.