KNK437

KNK437 (218924-25-5) Inhibits constitutive and inducible HSP70 expression in non-stressed1 and heat-stressed2 cancer cells. Blocks the geldanamycin-induced induction of HSP70 and inhibition of TGF signaling.3 Inhibits leukocyte integrin α47-mediated adhesion of T cells to mucosal addressin cell adhesion molecule 1 (MAdCAM-1) suggesting that HSP70 is essential for 7 integrin signalling.4 Suppresses morphine analgesic tolerance in a rodent model (100 mg/Kg).5

KNK437 has been used:

• as a heat shock factor 1 (HSF1) inhibitor to study its effects on the inhibition of viability and apoptosis activation in chemoresistant mice cells
• as an HSF1 inhibitor to study its effects on viability and apoptosis of colorectal cancer cells
• as a heat shock protein 70 (HSP70) inhibitor to study its effects on glutamine-induced HSP70 and inflammatory mediator release

KNK437 is a pan-HSP inhibitor that inhibits the synthesis of inducible HSPs, including HSP105, HSP72, and HSP40.

KNK437 inhibits the accumulation of heat shock proteins (including hsp -27, -40, -70, -72 and -105). KNK437 inhibits thermotolerance in cells with greater potency than quercetin.

In COLO320DM (human colon cancer) cells, KNK437 dose-dependently inhibits acquisition of thermotolerance and the activity of various HSPs, including Hsp105, HSP70 and HSP40. In PC-3 cells, KNK437 and quercetin dose-dependently inhibited thermotolerance. In PC-3 and LNCaP cells, KNK437 reduced heat-induced accumulation of HSP70 mRNA and protein.

KNK437 (200 mg/kg, intraperitoneal injection) showed no antitumor effect and did not increase the thermosensitivity of non-tolerant tumors. The same dose of KNK437 can synergistically improve the antitumor efficacy of graded heat treatment.

[1] MASAYUKI SHIOTA. Heat shock cognate protein 70 is essential for Akt signaling in endothelial function.[J]. Arteriosclerosis, Thrombosis, and Vascular Biology, 2010, 30 3: 491-497. DOI:10.1161/atvbaha.109.193631
[2] S YOKOTA  K N  M Kitahara. Benzylidene lactam compound, KNK437, a novel inhibitor of acquisition of thermotolerance and heat shock protein induction in human colon carcinoma cells.[J]. Cancer research, 2000, 60 11: 2942-2948.
[3] CHANG-HYUN YUN . Geldanamycin inhibits TGF-β signaling through induction of Hsp70[J]. Archives of biochemistry and biophysics, 2010, 495 1: Pages 8-13. DOI:10.1016/j.abb.2009.12.003
[4] Leukocyte integrin α47 associates with heat shock protein 70
[5] WANGJUN QIN. Effect of heat shock protein 70 modulators on the development of morphine analgesic tolerance in rats[J]. Behavioural Pharmacology, 2019, 31 1: 179-185. DOI:10.1097/fbp.0000000000000528