Objective: Proviral integration site for moloney murine leukemia virus (PIM) kinases are among the contemporary targets for cancer chemotherapy as they play a pivotal role in inhibition of apoptosis and oncogenic signaling. Owing to their structural and functional dissimilarity to other kinases, they can be specifically targeted. The present study is an attempt to establish three dimensional quantitative structure activity relationship (3D QSAR) between some 5-(1H-Indol-5-yl)-1,3,4-thiadiazol-2-amines for their inhibitory activity against PIM by partial least squares regression (PLSR) analysis. Method: PLSR coupled with different variable selection methods such as stepwise (forward-backward) (SW), genetic algorithm (GA) and simulated annealing (SA) was performed to derive QSAR models and these models were validated for statistical significance internally and externally and robustness. Results: Two most significant models were generated through GA with optimum values of validation parameters. Among these model 1 exhibited q 2 and pred_r 2 values of 0.7523 and 0.8714 and model 2 evinced 0.6577 and 0.7675 respectively. The steric field point in model 1 suggests the need of more bulky group at this position and the positive coefficients of electrostatic field points at positions E_999, E_1162 respectively indicate the need of electronegative groups for favorable biological activity. Model 2 suggests the requirement of a positive hydrophobic group at H_564 and less electronegative and more electronegative group at E_157 and E_630 respectively for more potent biological activity. Conclusion: More bulky and/or hydrophobic R groups apart from the electrostatic contribution may be favorable for better PIM-1 inhibition of 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2 amines. Key words: 1,3,4-Thiadiazole-2-amine, PIM, QSAR, Anticancer, PLSR. Key MessageThe quantitative structure activity relationship analysis on 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2 amines was carried out for PIM-1 inhibitory activity. The present study suggested the requirement of steric bulk and/or hydrophobic group at third position of indole ring for better activity.