The HCK/BTK inhibitor KIN-8194 is active in MYD88-driven lymphomas and overcomes mutated BTKCys481 ibrutinib resistance.

Activating mutations in MYD88 promote malignant cell growth and survival through hematopoietic cell kinase (HCK)-mediated activation of Bruton tyrosine kinase (BTK). Ibrutinib binds to BTKCys481 and is active in B-cell malignancies driven by mutated MYD88. Mutations in BTKCys481, particularly BTKCys481Ser, are common in patients with acquired ibrutinib resistance. We therefore performed an extensive medicinal chemistry campaign and identified KIN-8194 as a novel dual inhibitor of HCK and BTK. KIN-8194 showed potent and selective in vitro killing of MYD88-mutated lymphoma cells, including ibrutinib-resistant BTKCys481Ser-expressing cells. KIN-8194 demonstrated excellent bioavailability and pharmacokinetic parameters, with good tolerance in rodent models at pharmacologically achievable and active doses. Pharmacodynamic studies showed sustained inhibition of HCK and BTK for 24 hours after single oral administration of KIN-8194 in an MYD88-mutated TMD-8 activated B-cell diffuse large B-cell lymphoma (ABC DLBCL) and BCWM.1 Waldenström macroglobulinemia (WM) xenografted mice with wild-type BTK (BTKWT)- or BTKCys481Ser-expressing tumors. KIN-8194 showed superior survival benefit over ibrutinib in both BTKWT- and BTKCys481Ser-expressing TMD-8 DLBCL xenografted mice, including sustained complete responses of >12 weeks off treatment in mice with BTKWT-expressing TMD-8 tumors. The BCL_2 inhibitor venetoclax enhanced the antitumor activity of KIN-8194 in BTKWT- and BTKCys481Ser-expressing MYD88-mutated lymphoma cells and markedly reduced tumor growth and prolonged survival in mice with BTKCys481Ser-expressing TMD-8 tumors treated with both drugs. The findings highlight the feasibility of targeting HCK, a key driver of mutated MYD88 pro-survival signaling, and provide a framework for the advancement of KIN-8194 for human studies in B-cell malignancies driven by HCK and BTK.

[The curative effect of 1.8% hypertonic electrolyte glucose solution in enteral resuscitation of burn shock].

OBJECTIVE: To study the resuscitative effect of hypertonic electrolyte glucose solution (HEGS) in enteral resuscitation of burn shock. METHODS: Eighteen Beagle dogs with 35% TBSA full-thickness flame injury were used in this study. They were randomized to a control group (no-fluid resuscitation, N group), a HEGS resuscitation group (H group) or an isotonic electrolyte glucose solution (IEGS) resuscitation group (I group). The solution enterally was given for resuscitation from half an hour after burn. The volumes and rates of fluid infusion in the H group were basically in accordance with 2 ml/(kg x 1%TBSA), those in the I group were basically in accordance with parkland formula [4 ml/(kg x 1%TBSA)]. The haemodynamic parameters, global end-diastolic volume index, plasma volume, osmotic pressure of plasma, intestinal absorptive rates of water and Na(+), and intestine mucosa blood flow were continuously assessed. RESULTS: The cardiac output index, global end-diastolic volume index, plasma volume and intestine blood mucosa flow reduced markedly after burn in the three groups, and then gradually returned from 2 h after burn in two resuscitation groups, which were higher than that in the N group (P < 0.05). The activities of diamine oxidase in plasma in the two resuscitation groups were higher than that in N group (P < 0.05). The intestinal absorption rates of water and Na(+) reduced markedly after burn in two resuscitation groups with the lowest levels, and then returned from 6 h after burn. The rates of water in H group were lower than that in I group (P < 0.05); the rates of Na(+) in H group were higher than in I group (P < 0.05). CONCLUSION: The results indicated that 35%TBSA III degrees burn-injury dogs be resuscitated effectively with 1.8% hypertonic electrolyte-glucose solution by enteral, which 1/2 volume of an isotonic electrolyte glucose solution.

[Effects of early oral fluid resuscitation on hemodynamic and tissue perfusion during shock stage in dogs with a 50% total body surface area full-thickness burn.].

OBJECTIVE: To investigate the effect of early oral fluid resuscitation on hemodynamic and tissue perfusion in dogs with severe burn shock. METHODS: Eighteen male Beagle dogs with intubation of carotid artery, jugular vein, stomach, jejunum and bladder for 24 h were subjected to a 50%TBSA full-thickness burn, then were equally divided into non fluid resuscitation (NR), oral resuscitation (OR) and intravenous resuscitation(IR) groups, (each n = 6). Dogs in IR and OR groups were given glucose-electrolyte solution (GES) by gastric tube or intravenous infusion according to Parkland formula within 24 h after burn, while those in NR group were not given any treatment. Dogs in each group were given intravenous fluid resuscitation from 24 h after burn. The mean arterial pressure (MAP), cardiac output (CO), systemic vascular resistance (SVR), dp/dt max of left ventricular contractility (dp/dt(max)), gastric carbon dioxide pressure (PgCO2), intestinal mucosal blood flow (IMBF), and urinary output were determined before burn (0 h) and 2, 4, 8, 24, 48 and 72 h after burn at no anaesthesia state. Mortality rate of 72 h after burn was also recorded. RESULTS: MAP, CO, dp/dt(max), IMBF greatly decreased, and SVR and PgCO2 obviously increased from 2 h after burn in each group (P < 0.01). The measurements except IMBF of IR group returned to pre-injury levels at 72 h after burn, while CO, SVR, PgCO2 and IMBF of OR group still worse compared with 0 h (P < 0.01). All measurements of NR group kept on worsen, and died with anuria within 24 h after burn. Parameters of hemodynamic and tissue perfusion of OR group were significantly superior to those of NR group, but it inferior to those of IR group. At 72 h after burn, 6 (6/6) survived in IR group, 3 (3/6) in OR group and 0 (0/6) in NR group. CONCLUSIONS: Although oral resuscitation with GES is not as efficient as intravenous resuscitation in a 50%TBSA burn injury, it still can promote hemodynamic, improve the tissue perfusion and reduce the mortality comparing to no resuscitation. Oral resuscitation might be an ideal alternative way of intravenous resuscitation, especially in wars or other site of mass casualties.